BLOOD VESSELS (CHAPTER 11) (mespinosa)

Vascular Disorders
Responsible for more morbidity & mortality than any other category of human disease
Clinically significant lesions: artery & venous diseases
2 Prinicipal Mechanisms of Vascular Pathology:
1.
Narrowing (stenosis) / Complete Obstruction, either:
Progressively (atherosclerosis)
Precipitously (thrombosis/embolism)
2.
Weakening of vessel walls
Leads to dilation or rupture
STRUCTURE & FUNCTION OF BLOOD VESSELS
General architecture and cellular composition are the same throughout the CVS.
HOWEVER, certain features vary w/ & reflect distinct functional requirements at different
locations:
ARTERIAL WALLS generally thicker than walls of veins, to withstand the pulsatile flow &
higher blood pressure in arteries
Thickness diminishes(gradually) as the vessels become smaller
Thickness:Lumen Diameter (ratio) increases as vessels become smaller
Basic constituents of BV walls:
Endothelial Cells
Smooth Muscle Cells
Extracellular Matrix (ECM) + elastin, collagen & glycosaminoglycans
3 Concentric Layers:
1.
INTIMA
has single layer of endothelial cells w/ minimal underlying substance
connective tissue
separated from media by INTERNAL ELASTIC LAMINA (dense elastic membrane)
2.
MEDIA
SMOOTH MUSCLE CELL LAYERS: receive oxygen & nutrients from vessel lumen
(direct diffusion), facilitated by holes in the internal elastic membrane.
INADEQUATE DIFFUSION: Outer portions of media in LARGE & MEDIUM-SIZED
vessels
THEREFORE, nourished by small arterioles outside the vessel (VASA VASORUM
vessels of the vessels) which courses into outer - 2/3 of the media
OUTER LIMIT (most arteries): External Elastic Lamina
3.
ADVENTITIA
Consists of: connective tissue with nerve fibers & vasa vasorum

Muscular Arteries & Arterioles: regional blood flow & blood pressure is regulated by
changes in lumen size (vasoconstriction & vasodilation), controlled in part by ANS,
local metabolic factors & cellular interactions
3.

Small arteries 20 to 100um in diameter; within the substance of tissues & organs
ARTERIOLES: principal points of physiologic resistance to blood flow
Relative amount & configuration of basic constituents differ along the arterial system
owing to local adapatations to mechanical or metabolic needs. (Structural Variations at
MEDIA and ECM, principally)
CAPILLARIES (7-8um)
Have an endothelial cell lining but NO MEDIA
Have a very large total cross-sectional area
Flow rate SLOWS dramatically + thin walls, situated ideally to the rapid
exchange of diffusible substances between blood and tissues
Metabolically highly active tissues (eg MYOCARDIUM) have highest density of
capillaries
Blood (capillary bed)
postcapillary venules
collecting venules (vascular
leakage & leukocyte exudation occurs here in times of INFLAMM)
small veins
medium veins
large veins
VEINS
Larger diameters compared to arteries
Larger lumen
Thinner and less well organized walls
Predisposed to irregular dilation, compression and easy penetration by tumors
& inflamm processes due to poor support
Has a large capacity (CAPACITANCE VESSELS); 2/3 of blood is here
Reverse flow: prevented by venous valves
LYMPHATICS
Thin-walled, endothelium-lined channels
Serve as a drainage system for returning interstitial tissue fluid & inflammatory
cells to the blood
Constitute a pathway for disease dissemination

Based on Size & Structural Features

ARTERIES
1.
Large or ELASTIC ARTERIES aorta & its large branches(innominate, subclavian,
common carotid & iliac) & pulmonary arteries
MEDIA: rich in elastic fibers, allowing vessels to expand during systole & recoil during
diastole
propelling blood through peripheral vascular system
*AGING: arteries become proggressively TORTUOUS & DILATED (ECTATIC)
2.

Medium-sized or MUSCULAR ARTERIES other branches of aorta (coronary & renal

arteries)
MEDIA: composed predominantly of CIRCULARLY/SPIRALLY arranged smooth muscle
cells

Regional specializations of the vasculature. Although the basic organization of the vasculature is
constant, the thickness and composition of the various layers differ according to hemodynamic
forces and tissue requirements.
1

VESSELS DEVELOPMENT, GROWTH & REMODELING

3 Major Processes:
1.
VASCULOGENESIS
de novo formation of BVs druing embryogenesis
hemangioblast angiogenic prescursor: develop & migrate to sites of
vascularization
HAP
endothelial cells
primitive vascular plexus
definitive vascular system
VEGF: primary growth factors involved
Recruitement of Pericytes & Smooth Muscle Cells: required for the stabilization
of endothelial tubes during development (involves ANGIOPOIETIN 1 + Tie2
receptors)
2.
ANGIOGENESIS (NEOVASCULARIZATION)
New vessel formation in a mature organism
3.
ARTERIOGENESIS
Remodelling of existing arteries due to:
*chronic changes in pressure or flow
*from interplay of endothelial cell & smooth muscle cell derived factors
CONGENITAL ANOMALIES
Rarely symptomatic
DEVELOPMENTAL/BERRY ANEURYSM
Occur in cerebral vessels. When ruptured

fatal cerebral haemorrhage

ARTERIOVENOUS FISTULAS
Abnormal, typically small, direct connections between arteries & veins,
bypasses the intervening capillaries
Occur mostly as developmental defects
Can also result from:
*rupture of an arterial aneurysm to an adjacent vein;
*penetrating injuries that pierce arteries & veins;
*inflammatory necrosis of adjacent vesses
Intentionally created AV-Fistulas (used to provide vascular access for chronic
hemodialysis)
Rupture can also be an impt cause of intracerebral haemorrhage
Large/Extensive AV-fistulas shunts blood from arterial to venous circulations &
forces heart to pump additional volume
high output cardiac failure
FIBROMUSCULAR DYSPLASIA
Focal, irregular thickening of walls of medium & large muscular arteries (renal,
carotid, splanchnic, vertebral vessels)
Cause unknown but probably DEVELOPMENTAL (1st degree relatives
increased incidence)
Segments of vessel wall are focally thickened by combinations of irregular
medial & intimal hyperplasia & fibrosis
luminal stenosis (if in renal arteries
renovascular hypertension)
Vascular outpouchings (aneurysms) may develop
Manifests at any age; seen most frequently in young women
No association w/ use or oral contraceptives or abn of sex hormone expression

Vascular wall cells & their response to injury (rgau)

Endothelial and smooth muscle cells main cellular components of blood vessels; play central roles in pathology
Endothelial cells
Critical for maintaining vessel wall homeostasis & circulatory function
Contain weibel-palade bodies intracellular membrane bound organelles for Von willebrand factors (VWF)
Antibodies to VWF or PECAM-1 or CD31: used to identify endothelial cells immunohistochemically
Functions:
1.
Maintain a non-thrombogenic blood-tissue interface
2.
Modulate vascular resistance
3.
Metabolize hormones
4.
Regulate inflammation
5.
Affect growth of other cells (smooth muscle cells)
Interendothelial junctions: impermeable but can loosen under high BP, histamine

Endothelial cell properties and Functions

Maintains permeability barrier
Elaborates anticoagulant, antithrombotic,
fibrinolytic regulators

Elaborates prothrombotic molecules

Extracellular matrix production

Modulates blood flow and vascular reactivity
Regulates inflammation and immunity

Regulates cell growth

Vascular smooth muscle cells

Predominant cellular element of vascular media
Responsible for Normal vascular repair & patho processes atherosclerosis
Proliferates when properly stimulated
Can synthesize ECM collagen, elastin and proteoglycans
Elaborate GF and cytokines
Vasocon and vasodilation in response to physio/pharma stimuli
Migration and proliferation are regulated by:
Growth promoters
Growth inhibitors
Other regulators
PDGF
heparan sulfates
RAAS A2
Endothelin-1
NO
Catecholamines
FGF, IFN-y, IL-1
TGF-
Estrogen receptor, Osteopontin
Intimal thickening a stereotypic response to vascular injury

Prostacyclin
Thrombomodulin
Heparin-like molecules
Plasminogen activator
VWF
Tissue factor
Plasminogen activator inhibitor
Collagen
Proteoglycans
Vasoconstrictors: endothelin, ACE
Vasodilators: NO, prostacyclin
IL-1, IL-6, chemokines
Adhesion molecules: VCAM-1, ICAM-1, Eselectin, P-selectin
Growth stimulators: PDGF, CSF, FGF
Growth inhibitors: heparin, TGF-

Oxidizes LDL
Endothelial cells have phenotypic variability depending on anatomic site
Endothelial cells in liver sinusoids/renal glomeruli: fenestrated to facilitate filtration
CNS: impermeable BBB
Responds to pathophysiologic stimuli by adjusting their usual functions & expressing newly acquired
properties
ENDOTHELIAL ACTIVATION
INDUCERS of endothelial activation:
Cytokines & Bacterial products
Hemodyn stress & lipids
(atherosclerosis)
Glycosylation end products (DM)
Viruses, complement, hypoxia
ACTIVATED endothelial cells express
ADHESION MOLECULES
produce
cytokines, chemokines, GF, vasoactive
molecs, MHC, etc.
Left figure: normal endothelial function is
charac by a balance of these responses

Vascular injury (cell loss or just dysfunction) stimulates smooth muscle cell growth &
matrix synthesis that thickens intima
Neointima : healing of injured vessels results to this
During healing: medial sm muscle cells migrate into the intima, proliferate and
synthesize ECM
Neointima covered by endothelial cells
Neointimal smooth muscle cells
Do not contract
Can divide

Medial smooth muscle cells

Contract

Resoration/normalization of endothelial layer: initmal smooth muscle cells return to

non proliferative state but healing response results in permanent intimal thickening
Persistent / recurrent insults
excessive thickening
narrowing or stenosis of small
and medium sized BVs
impedes tissue perfusion
Note!
intimal thickening also occurs in normal arteries as a result of maturation and
aging
adult coronaries: intima and media are equal in thickness
age related intimal change: no consequences because of compensatory
outward remodeling of vessels
little change in luminal diameter
NOT ALL intimal thickening causes disease

Endothelial dysfunction: altered phenotype; rapid/delayed onset, reversible, independent

Impairs vasoreactivity/induces a surface that is thrombogenic or adhesive to inflamm cells
Thrombus formation, atherosclerosis, hypertensive vascular lesions
3

HYPERTENSIVE VASCULAR DISEASE (MBAJAMONDE)

congenital adrenal hyperplasia, licorice

ingestion)

blood pressure - a continuously distributed variable; the higher the pressure, the
greater the detrimental effects; no rigidly defined threshold level of blood pressure
distinguishes risk from safety
Low pressures (hypotension) - inadequate
organ perfusion and can lead to dysfunction or
tissue death

High pressures (hypertension) cause vessel and end-organ

damage

Accdg. to the National Heart, Lung, and Blood Institute of the U.S.A.:
sustained DP > 89 mm Hg / sustained SP > 139 mm Hg - associated with a measurably increased risk of atherosclerosis;
represent clinically significant hypertension
Both the SP and DP are important in determining cardiovascular risk
25% of individuals in the general population are hypertensive
Patients with other risk factors for vascular disease such as diabetes, have lower thresholds.
Mechanisms that result in hypertension remain largely unknown in most individuals in spite of an improved
understanding of the molecular pathways that regulate normal blood pressure.
essentialhypertension - multifactorial, resulting from the combined effects of multiple genetic polymorphisms
and interacting environmental factors
Prevalence and vulnerability to complications of HPN increase with age; higher in African Americans
Hypertension - one of the major risk factors for atherosclerosis and underlies numerous other diseases:
can cause cardiac hypertrophy and heart failure (hypertensive heart dse.), multi-infarct dementia, aortic
dissection, and renal failure
typically remains asymptomatic until late in its course and even severely elevated pressures can be
clinically silent for years.
Roughly half of hypertensive patients die of ischemic heart disease (IHD) or congestive heart failure (CHF), one
third die of stroke if left untreated
Prophylactic blood pressure reduction dramatically reduces the incidence and death rates from all forms of
hypertension-related pathology
secondary hypertension
5% have underlying renal or
adrenal disease
primary aldosteronism
Cushing syndrome
Pheochromocytoma
narrowing of renal artery, by
an atheromatous plaque
(renovascular hypertension)
other identifiable cause

Pheochromocytoma
Hypothyroidism (myxedema)
Pregnancy-induced

and oral contraceptives],

sympathomimetics and tyraminecontaining foods, monoamine oxidase
inhibitors)
Acromegaly
Hyperthyroidism (thyrotoxicosis)

5%, of hypertensives - show a rapidly rising blood pressure, leading to death within a year or two if untreated
accelerated or malignant hypertension syndrome; characterized by severe
hypertension:
SP> 200 mm Hg, DP > 120 mm Hg
renal failure
retinal hemorrhages and exudates
with or without papilledema
may develop in previously normotensive persons, often superimposed
on pre-existing benign hypertension, either essential or secondary
Regulation of Normal Blood Pressure
Blood pressure - a function of cardiac output and peripheral vascular resistance [hence, the formula: BP = CO x
PVR, with CO affected by SV and HR] (Fig. 11-4A )
Two hemodynamic variables that are influenced by multiple genetic, environmental, and demographic factors.
The major factors that determine blood pressure variation within and between populations: age, gender, BMI, and
diet (particularly sodium intake)

95% idiopathic (essential

hypertension)
- generally does not cause
short-term problems, it is
compatible with long life and
is asymptomatic when
controlled, unless MI, CVA, or
other complication
supervenes

TABLE 11-2 -- Types and Causes of Hypertension (Systolic and Diastolic)

ESSENTIAL HYPERTENSION (90% TO 95% OF CASES)
SECONDARY HYPERTENSION
Renal
Cardiovascular
Neurologic
Acute glomerulonephritis

Coarctation of aorta

Psychogenic

Chronic renal disease

Polycystic disease

Polyarteritis nodosa
Increased intravascular
volume
Increased cardiac output

Increased ICP
Sleep apnea

Renal artery stenosis

Renal vasculitis
Renin-producing tumors

Acute stress, including

surgery

Rigidity of the aorta

Endocrine
Adrenocortical hyperfunction (Cushing
Exogenous hormones (glucocorticoids,
syndrome, primary aldosteronism,
estrogen [including pregnancy-induced

Cardiac output - highly dependent on blood volume, greatly influenced by the sodium homeostasis
Peripheral vascular resistance - determined mainly at the level of the arterioles, affected by neural and hormonal
factors
4

Normal vascular tone - reflects the balance between:

humoral vasoconstrictors
vasodilators
angiotensin II
catecholamines
endothelin
Thromboxane
Neural factors ( 1-adrenergic)

kinins
prostaglandins, inc. prostacyclin (PGI2)
NO
ANP
Neuralfactors(2-adrenergic)

Resistance vessels exhibit autoregulation: increased blood flow induces vasoconstriction to protect against tissue
hyperperfusion
Other local factors:
pH and hypoxia & the- and -adrenergic systems - influence heart rate, cardiac contraction, and vascular tone,
are also important in regulating blood pressure
The (GOAL) integrated function of these systems: to ensure adequate perfusion of all tissues, despite regional
differences in demand.
1. Gene defects affecting enzymes in aldosterone metabolism
aldosterone synthase
11-hydroxylase
17-hydroxylase

2. Mutations affecting proteins that influence

sodium reabsorption
Liddle syndrome

- moderately severe form of salt-sensitive

hypertension, caused by mutations in an ENaC
protein DCTreabsorptionofsodiuminducedby
aldosterone
The KIDNEYS roles in blood pressure regulation as follows ( Fig. 11-4B ):
1. renin-angiotensin system - influences both peripheral resistance and sodium homeostasis
fallinBPRenin secretedbyJGcellsofkidneyreninconvertsplasma angiotensinogen to AI ACE then
converts AI to AII
Angiotensin II raises blood pressure by increasing both:
- peripheral resistance (direct action on vascular smooth muscle cells)
+
- blood volume (secrete aldosterone & increase DCT reabsorption of Na
2. prostaglandins and NO - produces a variety of vascular relaxing or antihypertensive, which presumably
counterbalance the vasopressor effects of angiotensin
3. WhenbloodvolumeisreducedGFR fallsincreasedreabsorptionofsodiumbyproximaltubules
conservation of sodium and expansion blood volume
4. Natriuretic factors (natriuretic peptides) - secreted by atrial and ventricular myocardium in response to
volume expansion, inhibit sodium reabsorption in DCT and cause sodium excretion and diuresis; induce
vasodilation and may be considered to represent endogenous inhibitors of the RAAS

lead to an aldosteronesecretionsaltandwater
resorptionplasmavolumeexpansionhypertension

Mechanisms of Essential Hypertension (No exact pathogenesis)

Genetic factors - definite role in determining blood pressure levels, shown by studies comparing blood pressure in
monozygotic and dizygotic twins, and of genetically related and adopted family members
single-gene disorders - cause relatively rare forms of hypertension (and hypotension) by altering net sodium
reabsorption in the kidney
Kidneys filter 170 liters of plasma containing 23 moles of salt daily; on a typical 100-mEq sodium diet, this means
that 99.5% of the filtered salt must be reabsorbed
98% of the filtered sodium is reabsorbed by a number of ion channels, exchangers, and transporters that are
constitutively active, not subject to regulation
remaining 2% of sodium is absorbed via the epithelial Na+ channel (ENaC), tightly regulated by the RAAS in the
cortical collecting tubule; this resorption pathway determines net sodium balance
Single-gene disorders cause severe but rare forms of hypertension through several mechanisms. These include:
There is an association of hypertension with polymorphisms in both the angiotensinogen locus and the angiotensin
receptor locus
Genetic variants in the RAAS may contribute to the known racial differences in blood pressure regulation
Reduced renal sodium excretion (meaning, aalat ang dugo ) with normal arterial pressure - key initiating event
in essential hypertension, final common pathway for the pathogenesis of hypertension

Initiating event: Decreased sodium excretion influidvolume(waterfollowswheresodiumis)COand

peripheralvasoconstrictionBPenoughadditionalsodiumwouldbeexcretedbythekidneysPurpose: to
equalintakeandpreventfurtherfluidretentionLater:analteredbutsteadystate of Na+ excretion is achieved,
butattheexpenseofaninbloodpressure(resettingofpressurenatriuresis kidneysperceiveBPas
normal)
vasoconstriction increaseinperipheralresistanceprimaryhypertension
Chronic or repeated vasoconstrictive influences could cause thickening and rigidity of the involved vessels [not only
the heart undergoes remodelling but also the vessels]
Environmental (exogenous) factors modify the impact of genetic determinants:
Stress
Obesity
Smoking
physical inactivity
heavy consumption of salt
Heavy sodium intake augments the condition in both essential and secondary hypertension
In summary:
essential hypertension - complex, multifactorial disorder, resulting from interactions of mutations or
polymorphisms at several loci influencing blood pressure & a variety of environmental factors (e.g., stress, salt
intake)
single gene disorders cause rare cases of HPN but not a major cause of essential hypertension
Mendelian forms of hypertension and hypotension are rare but yield insights into pathways and mechanisms
of blood pressure regulation, and help define rational targets for therapeutic intervention
Sustained hypertension requires participation of the kidney, by eliminating salt and water.
Susceptibility genes for essential hypertension unknown, but may include genes that govern responses to an
renalsodiumload,levelsofpressorsubstances,reactivityofvascularsmoothmusclecellsto
vasoconstrictive agents, or smooth muscle cell growth.
Hypertension both blood volume and peripheralresistance contribute to the increased pressure
(emphasized by Dr. Bongat)
Pathogenesis of Secondary Hypertension
Secondary hypertension - underlying pathways are reasonably well understood.
Examples:
a) renovascular hypertension
renalarterystenosisglomerularflow&pressureintheafferentarterioleoftheglomerulus:
(1) induces renin secretion, initiating angiotensin IImediated vasoconstriction and increased peripheral resistance
(2) increases sodium reabsorption and therefore blood volume through the aldosterone mechanism
b) Primary hyperaldosteronism - one of the most common causes of secondary hypertension
VASCULAR PATHOLOGY IN HYPERTENSION
Hypertension
accelerates atherogenesis
causes degenerative changes in the walls of large and medium arteries
can lead to aortic dissection and cerebrovascular haemorrhage
Morphology
2 forms of small blood vessel disease (Vascular Pathology) in HPN:
hyaline arteriolosclerosis
hyperplastic arteriolosclerosis
1) Hyaline Arteriolosclerosis
homogeneous, pink hyaline thickening with associated luminal narrowing d/t plasma protein leakage across injured
endothelial cells, and increased smooth muscle cell matrix synthesis in response to chronic hemodynamic stress
seen in the vessels of elderly persons (either normo- or hypertensive) but is more generalized and severe in
individuals with hypertension
Diabetic microangiography d/t hyperglycemia-induced endothelial cell dysfunction; same lesions are also a
common feature
5

Nephrosclerosis due to chronic hypertension: arteriolar narrowing of hyaline arteriosclerosis causes diffuse
impairment of renal blood supply and causes glomerular scarring
DrBongatsadditionalinfo:
- Usually occur in benign hypertension
- Complication: Chronic Renal Failure
2) Hyperplastic Arteriolosclerosis
occurs in severe (malignant) hypertension
vessels exhibit onion-skinlesions, characterized by concentric, laminated thickening of the walls and luminal
narrowing
laminations consist of smooth muscle cells with thickened, reduplicated basement membranes
malignant hypertension (SP> 200 mm Hg, DP > 120 mm Hg) - accompanied by fibrinoid deposits and vessel wall
necrosis (necrotizing arteriolitis), particularly in the kidney
DrBongatsadditionalinfo:
Malignant HPN that hasfibrinoidnecrosiscancausethrombosisaneurysm
This aneurysm can have 3 consequences:
Rupture
Ulceration
Haemorrhage
Three complications:
Hypertensive Heart Disease (HHD) cardiac hypertrophy and heart failure
Stroke (hemorrhagic type)
Acute Renal Failure and Uremia

Atherosclerosis
-

characterized by intimal lesions called atheromas (also called atheromatous or

atherosclerotic plaques) that protrude into vessel lumens.
consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and
cholesterol esters) covered by a white fibrous cap
Mechanically obstructing blood flow can rupture catastrophic vessel thrombosis
plaques also weaken the underlying media aneurysm formation.
coronary artery disease is an important manifestation of the disease.
Significant morbidity and mortality are also caused by
o
aortic and
o
carotid atherosclerotic disease
o
stroke

Epidemiology
Present among most developed nations
less prevalent in Central and South America, Africa, and parts of Asia.
US highest mortality rate for ischemic heart disease (IHD) about 5x than japan
Japan - IHD is the 2nd leading cause of death.
FIGURE 11-5 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; arrow)
causing lumenal obliteration
Arteriosclerosis (msperea)
literally means hardening of the arteries
it is a generic term reflecting arterial wall thickening and loss of elasticity.
There are three general patterns:
1.Arteriolosclerosis
Affects small arteries and arterioles, and may cause downstream ischemic injury.
2.Mnckeberg medial sclerosis
characterized by calcific deposits in muscular arteries in persons typically older than age
50.
The deposits may undergo metaplastic change into bone.
lesions do not encroach on the vessel lumen
not clinically significant
3.Atherosclerosis
Greek root words for gruel and hardening,
most frequent and clinically important

Major risk factors for Atherosclerosis

Non modifiable
Increasing age
Male gender
Family History
Genetic Abnormalities
Modifiable
Hyperlipidemia
Hypertension
Cigarette Smoking
Diabetes
C-Reactive protein
Constitutional risk factors in IHD. (less controllable)
Age
dominant influence.
Ages 40 and 60 the incidence of myocardial infarction increases fivefold.
Death rates from IHD rise with each decade even into advanced age.
Gender
premenopausal women protected against MI and other complications of
atherosclerosis (than in men) in the absence of risk factors such as
o
diabetes
o
hyperlipidemia
o
severe hypertension
Post menopausal - incidence of atherosclerosis-related diseases increases older ages
actually exceeds that of men.
Estrogen - proposed to explain the protective effect but some clinical trials have failed to
demonstrate any utility of hormonal therapy for vascular disease prevention.
6

atheroprotective effect of estrogens is related to the age at which the therapy is

initiated.
In younger postmenopausal women, there is a reduction in coronary atherosclerosis with
estrogen therapy.

Genetics
Family history is the most significant risk factor for atherosclerosis
Multifactorial, relating to inheritance of:
o
various genetic polymorphisms
o
hypertension
o
diabetes
Modifiable risk factors in IHD.
acquired or related to behaviors that are potentially amenable to intervention
Hyperlipidemia / hypercholesterolemia
major risk factor for atherosclerosis (can be independent and cause dse.)
Increase LDL(bad cholesterol) increase risk
LDL is delivered to peripheral tissues.
Increased (HDL, good cholesterol) reduced risk
In contrast HDL mobilizes cholesterol from tissue and transports it to the liver for excretion
in the bile
High dietary intake of cholesterol and saturated fats raises plasma cholesterol levels.
Diets low in cholesterol and/or with higher ratios of PUFA lower plasma cholesterol levels
Omega-3 fatty acids (abundant in fish oils) are beneficial,
trans-unsaturated fats adversely affect cholesterol profiles.
Exercise and moderate consumption of ethanol raise HDL levels,
Obesity and smoking lowers HDL
Statins
o
drugs that lower circulating cholesterol levels by inhibiting (HMG-CoA)
reductase
Hypertension
increases the risk of IHD by approx 60%
Hypertension is the most important cause of left ventricular hypertrophy
Cigarette smoking
well-established risk factor in men
Accounts for the increasing incidence and severity of atherosclerosis in women.
Prolonged (years) smoking doubles the death rate from IHD.
Smoking cessation reduces the risk substantially.
Diabetes mellituss
induces hypercholesterolemia markedly increases the risk of atherosclerosis.
Risk is 2x in diabetics vs. non diabetics
increased risk of strokes
100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities.
Additional risk factors.
Inflammation
present during all stages of atherogenesis
linked with atherosclerotic plaque formation and rupture
C-reactive protein (CRP)
one of the simplest and most sensitive markers of inflam. correlate with IHD risk
CRP is an acute-phase reactant synthesized primarily by the liver.
plays a role in the innate immune response by opsonizing bacteria and activating
complement.
When CRP is secreted from cells within the atherosclerotic intima activate local
endothelial cells induce a prothrombotic state increase the adhesiveness of
endothelium for leukocytes.
predicts the risk of :
o
myocardial infarction
o
stroke
o
peripheral arterial disease
o
sudden cardiac death, even among apparently healthy individuals
No direct evidence that lowering CRP directly reduces cardiovascular risk.

Smoking cessation, weight loss, and exercise reduce CRP

statins reduce CRP levels

Hyperhomocystinemia.
Clinical and epidemiologic studies show a strong relationship between total serum
homocysteine levels and coronary artery disease, peripheral vascular disease, stroke, and
venous thrombosis.
Elevated homocysteine levels can be caused by low folate and vitamin B 12 intake,
Homocystinuria
o
due to rare inborn errors of metabolism
o
results in elevated circulating homocysteine (>100 mol/L) and premature
vascular disease
Metabolic syndrome.
abnormalities that are associated with insulin resistance.
abnormal adipose tissue signaling has been proposed to drive the syndrome.
Dyslipidemia leads to endothelial cell dysfunction secondary to increased oxidative
stress
Lipoprotein (a)
altered form of LDL
contains the apo B-100 portion of LDL linked to apo-A.
Lipoprotein (a) levels are associated with coronary and cerebrovascular disease risk,
independent of total cholesterol or LDL levels.
Factors affecting hemostasis.
both are increasingly recognized as major contributors to local vascular pathology
o
Thrombin
o
Platelet-derived factors
Other factors.
Factors associated with a less pronounced and/or difficult-to-quantitate risk include
o
lack of exercise
o
competitive, stressful life style (type A personality)
o
obesity (which is often associated with hypertension, diabetes,
hypertriglyceridemia, and decreased HDL).
Pathogenesis of Atherosclerosis (jmvecida)
2 Hypotheses:
-

Intimal Cell Proliferation

Repetitive formation and organization of thrombi

Response to Injury Hypothesis

-

Atherosclerosis is a chronic and healing response of arterial wall to injury

Lesion progression through interaction of:
o
Modified lipoproteins
o
Monocyte derived macrophage
o
T lymphocytes

Events in Atherosclerosis
-

Endothelial injury, which causes:

o
Increased vascular permeability
o
Leukocyte adhesion
o
Thrombosis
Accumulation of lipoproteins (mainly LDL) in vessel wall
Monocyte adhesion to the endothelium followed by:
o
Migration to intima
o
Transformation to macrophage and foam cells
7

Platelet adhesion
Factor release from activated platelets, macrophages, and vascular cell walls
o
Leads to SMOOTH MUSCLE RECRUITMENT from TUNICA MEDIA or circulating
precursors
Smooth muscle cell proliferation and ECM production
Lipid accumulation both extracellularly and within cells

Endothelial Injury
-

CORNERSTONE OF RESPONSE TO INJURY HYPOTHESIS

Causes of endothelial loss:
o
Mechanical denudation
Result: Intimal
o
Hemodynamic forces
thickening
o
Immune complex deposition
o
Irradiation
o
Chemicals
If these factors are combined with HIGH LIPID DIETS ATHEROMA FORMATION
Intact endothelium site of early lesions
What happens in endothelial dysfunction:
o
Dysfunctional endothelial cells show:
Increased endothelial permeability
Enhanced leukocyte adhesion
Altered gene expression
Factors leading to endothelial dysfunction
2 most important
o
Hypertension Hemodynamic forces
causes of endothelial
o
Hyperlipidemia hypercholesterolemia
dysfxn
o
Toxins from cigarette smoke
o
Homocysteine
o
Infectious agents
Inflammatory cytokines (TNF) stimulate pro atherogenic patterns of endothelial cell gene
Expression

Hemodynamic Disturbances
-

Non-turbulent vasculature produces endothelial genes that protect against

atherosclerosis Superoxide Dismutase
Plaques tend to occur at locations of DISTURBED FLOW PATTERNS:
o
ostia of exiting vessels
o
branch points
o
posterior wall of abdominal aorta
o
Blood flow here is TURBULENT

Lipids
-

Transported in bloodstream bound to specific apoproteins

Dyslipoproteinemia:
o
mutations in apoproteins or receptors
o
disorders that affect circulating levels
nephrotic syndrome
alcoholism
hypothyroidism
DM
Common lipoprotein abnormalites:
o
Increased LDL
o
Decreased HDL
o
Increased Lp(a)

Hypercholesterolemia in Atherosclerosis
-

Dominant lipids cholesterol and cholesterol esters

Genetic defects in lipoprotein uptake and metabolis accelerated atherosclerosis
o
Homozygous Familial Hypercholesterolemia defective LDL receptors and LDL
uptake
MI before 20 years old
Level of cholesterol and severity of atherosclerosis are directly related
TX: lower serum cholesterol by diet or diet
Chronic hypercholesterolemia - increases oxygen free radical production
o
Injury to vessels
o
Nitric oxide decay decreased vasodilation
o
Accumulation of lipoprotein in TUNICA INTIMA
These lipids are oxidized by free radicals (from macrophage or
endothelial cells)
Ingestion by macrophage through SCAVENGER RECEPTORS
Accumulated lipids in macrophage FOAM CELLS
o
Oxidized LDL stimulates release of GF, cytokines
Further MONOCYTE recruitment
o
Oxidized LDL is cytotoxic to endothelial cells and smooth muscle cells
o
OXIDIZED LDL accumulates within MACROPHAGES in ALL STAGES of plaque
formation

Inflammation
-

Endothelial dysfunction expression of adhesion molecule (VCAM-1)

o
Encourage leukocyte adhesion
o
Binds monocytes and t-cells
Monocyte transforms to MACROPHAGE ENGULF OXIDIZED LDL
o
Theoretically protective, but,
o
OXIDIZED LDL increases macrophage activation and cytokine production (TNF)
o
Further increase in leukocyte adhesion and cytokines
Activated macrophage also produce ROS
o
Aggravates LDL oxidation
o
Elaborates GF smooth muscle proliferation
T-lymphocytes generates chronic inflammatory state, interacts with macrophages
o
Elaborate inflammatory cytokines (IFN-Gamma)
Stimulates macrophages, endothelial cells, smooth muscles

Infection
-

Herpesvirus
Cytomegalovirus
Chlamydia pneumonia also associated with smoking related broinchitis Risk factor for
Ischemic Heart Dse

Smooth Muscle Proliferation

-

Smooth muscle proliferation + ECM deposition converts fatty streak to mature atheroma
Growth factors involved in smooth muscle cell proliferation and ECM synthesis:
o
PDGF from platelets, macrophages, endothelial cells, smooth muscle cells
o
FGF
o
TGF-alpha
Smooth muscle cells synthesize ECM, mainly collagen, that STABILIZES atherosclerotic
plaques

Overview
-

Chronic inflammatory response vascular healing, driven by:

o
Endothelial cell injury
o
Lipid accumulation, oxidation
o
Thrombosis
Atheromas dynamic lesions consisting of:
o
Dysfunctional endothelial cells
o
Recruited and proliferating smooth muscle cells
o
Admixed lymphocytes and macrophages
o
All these cells release mediators that influence atherogenesis
Early stage: plaque smooth muscle + foam cells
Progression: atheroma modified by ECM
Fibrous cap connective tissue in intima
Central core of lipid laden cells and fatty debris that can calcify
May eventually encroach vessel lumen
Compress or degenerate media
Disruption: thrombosis and acute vascular occlusion

Clinically important changes in atheroma

-

Morphology
Fatty Streaks
-

Earliest lesions composed of lipid filled foamy macrophages

Multiple minute yellow spots, may elongate up to 1cm or more
Not raised, does not cause any flow disturbance
Aorta of infants <1yr show fatty streaks
Seen virtually in all children >10yrs
Evolves to atheroma, but not all
Coronary fatty streaks starts during adolescence

Atherosclerotic Plaque
-

Intimal thickening + lipid accumulation

Impinge on lumen of artery
Gross: appear white to yellow
o
0.3-1.5cm, can be larger
o
Thrombus red-brown
Patchy, only in a portion of arterial wall, eccentric
Flow disturbances (turbulence at branch points) Inc. susceptibility
Involved arteries, descending order:
o
Abdominal aorta Aortic aneurysms
o
Coronary arteries myocardial infarction
o
Popliteal arteries peripheral vascular disease
o
Internal carotid arteries cerebral infarction
o
Vessels of circle of willis cerebral infarction
o
Upper extremity arteries spared, except at ostia
Three principal components of plaque
o
Cells macrophage, smooth muscle cells, T cells
o
ECM collagen, elastic fibers, proteoglycans
o
Intra/extracellular lipid
Structure:
o
Superficial fibrous cap and dense collagen
o
Beneath: cellular area
o
Deep: necrotic core
Lipid
Dead cell debris

Foam cells
Fibrin
Thrombus
Cholesterol crystalline aggregates washed out during preparation
clefts
o
Periphery neovascularization
Plaques change due to cell death and degeneration, synthesis of ECM, organization of
thrombus
Atheroma may calcify

Rupture, ulceration, erosion of INTIMA

o
Exposure to highly thrombogenic substances, thrombosis, partial or complete
occlusion
o
Downstream ischemia
o
Clot may be incorporated to the plaque
Hemorrhage into a plaque
o
Rupture of overlying cap or area of neovascularization intraplaque
haemorrhage
o
Expansion of atheroma
Atheroembolism
o
Discharge of atherosclerotic debris
o
Microemboli
Aneurysm formation
o
Pressure, ischemic atrophy of media
o
Loss of elastic tissue
o
Weakness aneurysmal dilatation and rupture

Consequences of Atherosclerosis (mcvelasco)

Major Targets of Atherosclerosis:
1.
2.

Large arteries- aorta, carotid & iliac arteries

Large & medium-sized muscular arteries- coronary & popliteal artery

Symptomatic Atherosclerosis most commonly involved:

Heart, brain, kidney & lower extremities
Major Consequences of Atherosclerosis
1.
2.
3.
4.

MI (heart attack)
Cerebral infarction (stroke)
Aortic aneurysms
Peripheral vascular disease (gangrene of the legs)

The principal outcomes depend on the size of involved vessels, the relative stability of the plaque
itself & the degree of degeneration underlying arterial wall:
Smaller vessels can be occluded, compromising distal tissue perfusion
Ruptured plaque can embolize atherosclerotic debris & can cause distal vessel
obstruction or can lead to acute vascular thrombosis
Destruction of the underlying vessel wall can lead to aneurysm formation w/ secondary
rupture &/or thrombosis
9

Atherosclerotic Plaque

thin fibrous cap (undergoes remodeling), few smooth muscle cells or cluster of
inflammatory cells

Small Arteries
atherosclerotic plaques can gradually occlude vessel lumens compromising blood
flow & causing ischemic injury
Early Stages: outward remodeling of the vessel media tends to preserve luminal diameter as the total
circumference expands

vulnerable plaques
Collagen
Major structural component of the fibrous cap
Accounts for its mechanical strength & stability balance btwn its synthesis &
degradation affects stability
In atherosclerotic plaque
produced primarily by smooth muscle cells
loss of these
results to weakening of the cap
Collagen turnover:
a.
controlled by MMPs & enzymes elaborated largely by macrophages w/in the
atheromatous plaque
b.
Tissue inhibitor of MMP produced by endothelial cells, smooth muscle cells &
macrophages
modulate MMP activity

w/ limits on outward remodeling & eventually the expanding atheroma impinges on blood flow
Critical Stenosis- Rubicon at w/c chronic occlusion significantly limits flow & demand begins
exceedingly supply
In Coronary Circulations- it occurs at approx. 70% fixed occlusion; at this degree patients classically
develop chest pain/angina on exertion
Stable Angina
Chronically diminished arterial perfusion:
Mesenteric occlusion & bowel ischemia, chronic IHD, ischemic encephalopathy &
intermittent claudication
All are consequence of limiting stenosis

Plaque Inflammation
net increase in collagen degradation & reduces collagen synthesis
destabilizing the mechanical integrity of the fibrous cap
Statins: beneficial therapeutic effect not only by reducing circulating cholesterol levels but also by
stabilizing plaques through reduction in plaque inflammation

The effect of vascular occlusion ultimately depends on arterial supply & metabolic demand of the
affected tissues.
Acute Plaque Change
Plaque erosion/rupture is typically promptly followed by partial or complete vascular thrombosis
acute tissue infarction
Plaque changes fall into 3 categories:
Rupture/fissuring, exposing highly thrombogenic plaque constituents
Erosion/ulceration, exposing thrombogenic subendothelial bm to blood
Hemorrhage in atheroma, expanding its volume
It is now recognized that the precipitating lesion in px who develop MI & other acute coronary
syndromes is not necessarily a severely stenotic & hemodynamically significant lesion before its acute
change.
Pathological & Clinical Studies
majority of plaques undergo abrupt disruption & coronary
occlusion previously showed only mild to moderate luminal stenosis

Extrinsic Influences:
1.

Adrenergic Stimulation
-increase systemic bp or induce local vasoconstriction
increase physical stress on the
plaque
-associated w/ walking & rising
bp spikes
linked to pronounced circadian periodicity
for the peak time of onset of acute MI
6am to 12 nn

2.

Intense Emotional Stress

-can also contribute to plaque disruption

Not all plaque ruptures result in occlusive thromboses w/ catastrophic consequences

Plaque disruption, platelet aggregation & thrombosis: common, repetitive & clinically silent
complicationsof atheroma
Thrombosis

Conclusion: rather large number of now asymptomatic adults may well have a real but
unpredictable risk of catastrophic coronary events
Events Triggering Abrupt Changes in Plaque Configuration & Superimposed Thrombosis:
Complex
Include both intrinsic & extrinsic factors
Rupture of plaque
unable to withstand the mechanical stress of vascular shear forces
Composition of Plaques
Dynamic
Contribute to risk of rupture
w/ large foam cells & extracellular lipids

-critical to the pathogenesis of acute coronary syndromes

Serious forms: it superimposed on a disrupted but previously only partially stenotic plaque
occlusion

total

In others: incomplete & can even wax & wane with time
Mural Thrombus in coronary artery can also embolize
-potent activator of multiple growth-related signals in smooth muscle cells
atherosclerotic lesions

growth of
10

Vasoconstriction
-compromises lumen size & by increasing the local mechanical forces can potentiate plaque
disruption
Vasoconstriction at site of atheroma is stimulated by:
1.
Circulating adrenergic agonist
2.
Locally released platelet contents
3.
Impaired secretion of endothelial cell relaxing factors (NO) relative to contracting factors
(endothelin) as a result of endothelial cell dysfunction
4.
Mediators released from perivascular inflammatory cells

Aneurysm and Dissection (rgau)

Aneurysm
Localized abnormal dilation of a blood vessel or the heart
Congenital OR acquired
True Aneurysm

False Aneurysm

- pseudo-aneurysm
- Defect in the vascular wall leading to an
extravascular hematoma that
communicates with intravascular space
pulsating hematoma
- the wall is ruptured
collection of blood
(hematoma) that is bounded externally by
adherent extravascular tissue
- Examples:
Ventricular rupture after MI

Involves an intact attenuated arterial wall

or thinned ventricular wall of the heart
Examples:
Atherosclerotic aneurysms
Syphilitic aneurysms
Congenital vascular aneurysms
Ventricular aneurysm that follow
transmural MI

Classification by shape and size (not specific for any disease or manifestations)
Saccular
- Spherical outpouchings (involves only a
portion of the vessel wall)
- Often contain thrombus

Fusiform aneurysms
- Diffuse, circumferential dilation of a long
vascular segment
- Can involve aortic arch, abdominal aorta
or iliac arteries

Dissection
Arises when blood enters the arterial wall itself, as a hematoma dissecting between its layers
Often but not always aneurysmal
Blood enters the dissected wall of the vessel & separate the layers
Note:
Both true, false and dissections CAN RUPTURE, often with catastrophic consequences

Pathogenesis of aneurysms:
Arteries maintain their integrity by constantly synthesizing, degrading & repairing damage to
their ECM constituents
Aneurysms occur when the structure or function of the connective tissue within vascular wall is
compromised
Weakening of vessel walls is important in common, sporadic forms of aneurysms
Intrinsic quality of the
Marfan Syndrome
vascular wall connective
Defective synthesis of fibrillin leads to aberrant TGF- activity
tissue is poor
progressive weakening of elastic tissue
Aorta : progressive dilation due to remodeling of inelastic
media
Loeys-Dietz syndrome
Mutations in TGF- receptors lead to abnormalities in elastin &
collagen I & II
Aneurysms rupture easily (even at small size)
Ehlers-Danlos syndrome
weak vessels due to defective type III collagen synthesis
(hallmark)
causes aneurysm
11

Balance of collagen
degradation & synthesis is
altered by local
inflammatory infiltrates &
the destructive
proteolytic enzymes they
produce
Vascular wall is
weakened through loss of
smooth muscle cells /
inappropriate synthesis of
noncollagenous/nonelastic ECM

Altered collagen cross-linking associated with Vit. C deficiency

causes aneurysm
Increased MMP production (by macrophages in atherosclerosis / in
vasculitis)
contributes to aneurysm development
MMPs degrade components of the ECM in the arterial wall
(collagens, elastin, proteoglycans, laminin, fibronectin)
Decreased TIMP (tissue inhibitor of MMP): ECM degradation
Polymorphisms of MMP or TIMP genes: genetic predisposition
for aneurysm
Atherosclerotic thickening of intima
increase distance that
oxygen & nutrients must diffuse
ischemia of inner media
Systemic hypertension
narrowing of arterioles of vasa vasorum
(in the aorta)
outer media ischemia
Ischemia: reflected in degenerative changes of the aorta
Smooth muscle cell loss / change in synthetic phototype
leads to:
1.
scarring (loss of elastic fibers)
2.
Inadequate ECM synthesis
3.
Production of many amorphous ground subs
(glycosaminoglycan)
cystic medial degeneration collective term for 1-3
These changes are nonspecific & can be seen in other
cases (Marfans & Scurvy)

Two most important disorders that predispose to aortic aneurysms:

1.
Atherosclerosis greater factor in abdominal aortic aneurysms
2.
Hypertension most common condition associated with ascending aorta aneurysms
Other conditions that weaken vessel walls & lead to aneurysms:
1.
Trauma
2.
Vasculitis
3.
Congenital defects (berry aneurysms in the Circle of Willis)
4.
Infections (mycotic aneurysms)
Mycotic aneu can originate:
a.
From embolization of a septic thrombus as a complication of infective
endocarditis
b.
As an extension of an adjacent suppurative process
c.
By circulating organisms directly infecting arterial wall
5.
Tertiary syphilis rare cause of aortic aneu
Late stage syphilis has obliterative endarteritis that affects small vessels including vasa
vasorum of thoracic aorta
leads to ischemia of aortic media & aneurysmal dilation (may
involve aortic valve annulus)

Debakey classifications of
Aortic dissection (next
page)

12

ANEURYSMS
Disease
Abdominal Aortic
Aneurysm (AAA)

Definition / Epidemiology
Associated with atherosclerosis
Major cause of AAA
At risk of IHD & stroke
MMP from inflamm cell infiltrates
Major influence that leads to aneurysm
Frequent in men & in smokers, rarely
before age 50
Two variants:
1.
Inflammatory AAAs (+) dense
periaortic fibrosis with lymphoplastic
inflamm with many macrophages & giant
cells
Cause uncertain
2.
Mycotic AAAs lesions that are infected
by microorgs that lodge in the wall
(primary Salmonella gastroenteritis)
suppuration futher destroys media
rapid dilation & rupture

Thoracic Aortic
Aneurysm

Pathogenesis
Athero plaque in the intima
compresses media

Compromises nutrient and waste

diffusion from vascular lumen into
arterial wall

Media undergoes degeneration &

necrosis

Arterial wall weakens & thins out

Morphology / Characteristics
Positioned below renal arteries &
above bifurcation of aorta
Can be saccular or fusiform
15 cm in diameter & 25 cm in length
Intima of the aneurysm (+) severe
atherosclerosis with destruction &
thinning of underlying media
Aneurysm contains: bland,
laminated, poorly organized mural
thrombus that may fill some or all of
dilated segment
Can affect renal & superior / inferior
mesenteric arteries by direct
pressure / by narrowing or
occluding vessel ostia with mural
thrombi
Accompanied by smaller aneurysms
of iliac arteries

Clinical Features / Ssx

1.
Fatal hemorrhage due to rupture into
peritoneal cavity or retroperitoneal tissues
2.
Ischemic injury of tissues
Iliac (leg)
Renal (kidney)
Mesenteric (GIT)
Vertebral (SC) arteries
3.
Embolism from atheroma or mural thrombus
4.
Impingement on adjacent structure
compress ureter or vertebral erosion
5.
Abdominal mass palpably pulsating that
simulates a tumor
Risk of rupture directly related to size
Expands at a rate of 0.2-0.3 cm/yr
Aneu 5cm and larger surgical bypass with
prosthetic grafts
Endoluminal stent grafts
Timely surgery is critical

Associated with hypertension

Other causes: Marfan & Loeys-Dietz

1.
2.

Syphilitic aneurysms die of heart failure

induced by aortic valvular incompetence

3.
4.
5.
6.
7.

Aortic
Dissection
dissecting
aneurysm older
term, avoided

Hypertension major risk factor

Occurs when blood splays apart the
laminar planes of media to form a bloodfilled channel within aortic wall
Catastrophic if it ruptures through
adventitia and hemorrhages into
adjacent spaces
May or may not be associated with aortic
dilation (in contrast to atherosclerotic &
syphilitic aneu)
Can be iatrogenic (during diagnostic
catheterization/ bypass)
Unusual if atherosclerosis is substantial /
there is medial scarring due to syphilis
because medial fibrosis inhibits
propagation of dissecting hematoma
Occurs in:
1.
Men aged 40-60 with hypertension
(90% of cases)
2.
Younger px with systemic or
localized connec tissue probs
affecting aorta (Marfan)
3.
During or after pregnancy
Some cases:
Disruption of penetrating vessels of v. vasorum
Has intamural hematoma without intimal tear

Aorta of hypertensive patients have

medial hypertrophy of vasa vasorum
diminished blood flow thru
v.vasorum
degen changes in
aortic media & loss of medial smooth
muscle cells
Inherited/ acquired connective tissue
disorders cause abnormal vascular
ECM
Marfan syndrome
Ehlers-Danlos syndrome
Vit C deficiency
Cu metab defects
Note!
Medial damage not a pre-req for
dissection nor makes dissection
imminent
Trigger for intimal tear & initial aortic
hemorrhage not known
Once tear is (+)
blood dissects
through media
pressure reducing
tx may be effective

Encroachment on mediastinal structures

Respi difficulties due to lung and airway
encroachment
Swallowing difficulties due to compression of
esophagus
Persistent cough due to irritation/pressure on
recurrent laryngeal nerves
Pain caused by erosion of bone (ribs & vertebral
bodies)
Cardiac disease due to aortic valve dilation with
valvular insufficiency or narrowed coronary ostia
MI
Rupture

No specific cause identified

Cystic medial degeneration most
frequent preexisting histologic lesion
Inflammation is absent

Risks and complications depend on region/s

affected
Most serious complic: dissections involving
aorta from the aortic valve to the arch

Initiates with an intimal tear majority

found in the ascending aorta within
10cm of the aortic valve
Tears are transverse or oblique,
1-5 cm with sharp, jagged edge
Dissection extend along the aorta,
retrograde toward the heart, or
distally into the iliac & femoral
arteries
Hematoma spreads between
middle & outer thirds of aorta
Ruptures through adventitia
causing:
1.
massive hemorrhage
(thoracic/abdominal cavities)
2.
cardiac tamponade
(pericardial sac)
hematoma may reenter lumen of
aorta thru a 2nd intimal tear
new
vascular channel
double
barreled aorta w/ a false channel
avert/avoid fatal hemorrhage

Manifestations:
Sudden excruciating pain (ant chest
back between the scapulae
downward)
Pain can be confused with that of MI
Cardiac tamponade
Aortic insufficiency
MI
Vascular obstruction
Transverse myelitis
Rupture of the dissection outward into
pericardial, pleural or peritoneal cavities
Most common cause of death
2 types of aortic dissections:
1.
Type A dissections (1 & 2 of Debakey)
more common & dangerous
Involves both ascending & descending
aorta / just the ascending aorta
2.
Type B dissections (2 of Debakey)
Distal lesions NOT involving ascending
part
Begins distal to subclavian artery
13

Vasculitis (rgau, cgs)

Vessel wall inflammation
Manifestations:
o
Depend on vascular bed affected (CNS vs heart VS small bowel)
o
Include constitutional signs & symptoms fever, myalgias, arthralgias, malaise
Vessels of any organ Can be affected but mostly involve small vessels from arterioles to
capillaries to venules
o
Affects aorta, medium sized arteries, smaller arterioles
Chapel Hill nomenclature: most widely accepted approach to organizing vasculitides
Type of Vasculitis
Large-vessel vasculitis

Aorta & large branches

to extremities, head &
neck
Medium vessel vasculitis

Main visceral arteries &

their branches

Small vessel vascultis

Arterioles, venules,
capillaries, occasionally
small arteries

MPO-ANCAs
- antineutrophilic cytoplasmic
Antibodies
- against myeloperoxidase (pANCA)
PR3-ANCAs
antineutrophilic cytoplasmic
antibodies
- against proteinase3 (c-ANCA)

Examples
Giant-cell
(temporal) arteritis

Takayasu arteritis

Polyarteritis nodosa

Kawasaki disease

Wegener
granulomatosis

Churg strauss
syndrome

Microscopic
poluangitis

Description
Granulomatous inflammation
Frequent: temporal artery
Patients > 50
Associated with polymyalgia
rheumatica
Granulomatous inflammation
Patients > 50

Necrotizing inflammation
Involves renal arteries
Spares pulmonary vessels
Arteritis with mucocutaneous
lymph node syndrome
In children
Involves coronary arteries with
aneurysm formation/thrombosis
Granulomatous inflammation
Involves respi tract
Necrotizing vasculitis
Small vessels(glomerular
vessels)
Associated with PR3-ANCAs
Eosinophil rich granulomatous
inflammation
Respi tract
Necrotizing vasculitis
Small vessels(glomerular
vessels)
Associated with
Asthma
Blood eosinophilia
MPO-ANCAs
Necrotizing small vessel vascultis
with few or no immune deposits

2 most common pathogenic mechanisms of vasculitis:

1.
Immune mediatedinflammation
2.
Direct invasion of vascular walls by infectious pathogens
o
Infections can also indirectly induce a non-infectious vasculitis
Generate immune complexes or triggering cross-reactivity
Critical to distinguish between infectious & immunological mechanisms
o
Immunosuppressive tx could worsen infectious vasculitis
Physical, chemical injury (irradiation, trauma, toxins) also cause vascultis

Necrotizing arteritis of small &

medium sized arteries can occur
Necrotizing glomerulonephritis &
pulmo capillaritis common
Associated with MPO-ANCAs

NOTE!
SMALL & LARGE VESSEL VASCULITIS: may involve medium-sized arteries
LARGE & MEDIUM SIZED VESSEL VASCULITIS: DO NOT involve vessels smaller than arteries

14

Disease
Non-infectious
vasculitis

1.

Type
Immune complex
associated vascultis

Pathogenesis
Antibody & complement
Ag-Ab complexes

Characteristics & Manifestations

lesions resemble those in arthus
reaction & serum sickness

Morphology

Clinical Features

immune complex deposition due to

drug hypersensitivity
Penicillin bind to serum proteins
Streptokinase foreign CHONs
Manifestations:
Seen in the skin
Mild/self limiting
severe/fatal
Discontinuation of drug lead to
resolution

2.
-

ANCA
Autoantibodies
c-ANCA or p-ANCA
antigenic targets are
intracellular
but PR3: (+) at low levels
on plasma membrane or
translocated to cell
surface in activated &
apoptotic neutrophils

ANCA activate neutrophils

neutron rel ROS &
proteolytic enzymes
endothelial-cell-neutrophil
interactions
endothelial
damage

3.
Giant-cell (Temporal
arteritis)
Most common
form in elderly

Anti-endothelial cell
antibodies
Chronic granulomatous
inflammation of large to smallsized arteries
HLA class 2 haplotypes
Response to steroids

ANCAs reacting with

neutrophil cytoplasmic Ag
Primary granules
Monocyte lysosomes
Endothelial cells

Secondary to viral infections

Ab to viral CHONs
Polyarteritis nodosa have
underlying hepa B that
produces vascultis due to
complexes of HBsAg & anti
HBsAg antibody
Anti-myeloperoxidase (MPO-ANCA):
- induced by therapeutic agents
(propylthiouracil)
p-ANCA
Polyangitis
Churg Strauss syndrome
Anti-proteinase (PR3-ANCA)
Homologous with microbial
peptides
c-ANCA
Wegener granulomatosis

Kawasaki disease
T cell mediated immune
response against an
unknown vessel wall antigen
Pro-inflamm cytokines
Anti-endothelial cell
humoral response

Affects arteries in the head

temporal arteries
Also affects vertebral & ophthalmic
arteries
Permanent blindness
Also occur in the aorta (giant cell
aortitis)
Medical emergency

Takayasu Arteritis
pulseless disease
Most frequent in

Granulomatous vasculitis of
medium and larger arteries

Mechanism: (not morphology!!!)

1.
Drugs/cross reactive microbial
antigens induce ANCAs
2.
Subsequent infection, endotoxin
exposure or inflammatory stimuli
elicit TNF
causes expression of
PR3 & MPO
3.
ANCAs react with cytokineactivated cells & cause direct
injury to endothelial cells or
induce further activation
(neutrophils)
4.
ANCA activated neutrophils
degranulate
rel ROS
injury

Unknown;

Ocular disturbances

Immune reactions
speculated

Marked weakening of pulses in upper

extremities

Nodular intimal thickening with

occasional thrombosis
Reduces lumen diameter
Medial granulomatous inflammation
leading to elastic lamina
fragmentation
Infiltrate of Tcells (CD4 > CD8) &
macrophages
(+) multinucleated giant cells
Panarteritis:
lymphocytes, macrophages
Inflammatory lesions:
not continuous along the vessel
Healed stage:
medial scarring, intimal
thickening
Most: aortic arch involvement
1/3: aortic arch + aorta and branches
involved

Rare before age 50

Vague & constitutio0nal sx:
fever, fatigue, weight loss
facial pain
headache intense in the
course of superficial
temporal artery painful to
palpitation
ocular symptoms
(ophthalmic artery)diplopia to blindness
A (-) biopsy does not exclude dx
Tx:
-

corticosteroids
anti- TNF tx

Initial: non-specific
- fatigue
- weight loss
- fever
15

women < 40 y.o.

- (d/t narrowed/ obliterated

great vessels when aortic
arch is involved)
- can happen in coronary and
renal arteries also

global, but
traditionally in
Japan

Transmural fibrous thickening of aorta

(aortic arch and great vessels)
Severe luminal narrowing of major
branch vessels
Variable course of disease:
- can have rapid progression or
- quiescent stage (1-2 yrs)
long term survival w/
neurological or visual deficits

Polyarteritis Nodosa
(PAN)
Disease of young
adults (but can
occur at any age)
Dx: biopsy
Tx:
cyclophosphamide
(90% remission or
cure)
Fatal if untreated
- during acute
fulminant or
- protracted course

Systemic vasculitis of small or

medium sized muscular arteries
- NOT arterioles,
capillaries, or venules
Usually involves renal or visceral
vessels
Spares pulmonary circulation

Unknown
Immune complex mediated
(HbsAg-HbsAb)
Different classes:
- classic idiopathic PAN
- cutaneous PAN
- PAN associated w/
chronic hepatitis

Segmental transmural necrotizing

inflammation of small to medium
sized arteries
Involvement of organs (descending
order of frequency):
1.
kidneys
2.
heart
3.
liver
4.
GI tract

No association w/ ANCA
Lesions only involve part of vessel
circumference w/ predilection for
branch points

30% of patients:
- (+) hep B antigenemia
- (+) HbsAg-HbsAb
complexes in lesions

Gross: intimal hyperplasia

Irregular thickening of
vessel wall
Possible changes:
- adventitial mononuclear
infiltrates w/ perivascular cuffing
of vasa vasorum
- intense mononuclear
inflammation in the media
- granulomatous inflammation w/
giant cells and patchy medial
necrosis
Histologically indistinguishable from
temporal arteritis
- distinguish giant cells in aorta
based on age of patient
- if < 50 y.o.
Takayasu aortitis
With disease progression:
- collagenous scarring w/
admixed chronic inflammatory
infiltrates (in all 3 layers)
- aortic root involvemt dilation &
aortic valve insufficiency
Inflammatory process
weakens
arterial wall
aneurysms or rupture
First sign: impaired perfusion w/
- ulcerations
- infarcts
- ischemic atrophy
- hemorrhages
Acute phase:
- Transmural inflammation of
arterial wall w/ neutrophils,
eosinophils, and mononuclear
cells
- fibrinoid necrosis
- possible luminal thrombosis
acute inflammatory infiltrate eventually
replaced by fibrous (or nodular)
thickening of vessel wall (can reach
adventitia)
All stages of activity can coexist in diff.
vessels or w/in same vessel
suggests
ongoing or recurrent pathogenic insults

Kawasaki Disease
Mucocutaneous LN
syndrome
Acute, febrile, selflimited illness of
infancy and

Arteritis affecting large to

medium sized (sometimes
small) vessels

Uncertain
Possibly genetic
Viral
Can be d/t delayed type
hypersensivity response of T
cells to unknown Ag

Involvement of coronary arteries

Coronary arteritis
aneurysm
rupture and thrombose
acute MI
Conjunctival and oral erythema and
erosions

PAN-like
- pronounced inflammation on
vessel wall
- less prominent fibrinoid
necrosis
Acute vasculitis:
- subsides spontaneously or in

Progression: vascular symptoms

- reduced BP
- weaker pulses in upper
extremities
- cold, numb fingers
- ocular disturbances (visual
defects)
- retinal hemorrhage
- total blindness
- neurologic deficits
w/ involvement of distal aorta
claudication of legs
w/ involvement of pulmonary
artery
pulmonary
hypertension
w/ involvement of renal artery
systemic hypertension
narrowed coronary ostia

MI

Course varies from acute,

subacute, or chronic, but usually
REMITTING and EPISODIC (has
long symptom free intervals)
Scattered vascular involvement
varied clinical findings
Most common manifestations:
- malaise
- fever
- weight loss
Other manifestations:
- hypertension (rapid)
- abdominal pain and melena
- diffuse muscular aches and
pains
- peripheral neuritis
(predominantly affects motor
nerves)
- renal arterial involvement
(major cause of death)
NO glomerular arteriolar
involvement
NO
glomerulonephritis
20%: develop CV sequelae if
untreated
asymptomatic
coronary arteritis
coronary artery
ectasia
aneurysm formation
giant coronary
16

childhood (80%
younger than 4)

Cytokine production and

macrophgae (+)

Leading cause of
acquired heart
disease in children

Microscopic
Polyangiitis
Hypersensitivity
vasculitis
Leukocytoclastic
vasculitis
Tx:
cyclophosphamide
- induces remission
- improves long
term survival
- EXCEPT if have
widespread renal
or brain
involvement
Churg-Strauss
Syndrome

B cell activation
Formation of auto-Ab in
endothelial cells and
smooth muscles

Necrotizing vasculitis
Segmental fibrinoid necrosis of
media w/ focal transmural
necrotizing lesions
generally affects:
- capillaries, arterioles,
and venules smaller
than those affected in
PAN

MPO-ANCA: casually
implicated

Most lesions are pauci-immune

(devoid of immune complexes

Recruitment and (+) of

neutrophils

Small vessel necrotizing

vasculitis

Obscure
Can result from hyperresponsiveness to allergic
stimulus

Angiitis

Asthmatics:
- trigerred by leukotriene
receptor antagonists

Rare (1:1M)

Limited form:
Restricted to
respiratory tract
Widespread form:
Affects eyes, skin,
other organs (esp.
heart)
Resembles PAN, but
w/ respiratory
involvement

Pathogenic immune
complex deposition or
trigger secondary immune
complex (devt of p-ANCA)

Rare involvement of large

arteries

Allergic
granulomatosis

Wegeners
Granulomatosis

Acute vasculitis
Ab response to Ag in:
- drugs (penicillin)
- microorganisms
(streptococci)
- heterologous proteins
- tumor proteins

Necrotizing vasculitis

T-cell mediated
hypersensitivity rxn
(+) granuloma and response
to immunosuppressive
therapy = possibly from
inhalation of infectious or
environmental agent
PR3-ANCA:
- (+) in 95% of cases
- marker for disease
- participates in
pathogenesis
Relapse:
- rise in PR3-ANCA after
immunosuppressive
therapy

Edema of hands and feet

response to Tx

Erythema of palms and soles

Aneurysm, thrombosis, MI: supervene!

Desquamative rash

Healed lesions have obstructive intimal

thickening

Cervical LN enlargement

Rare pathologic changes out of CVS

All lesions tend to be of the same age

in any patient
Involvement of:
- skin and mucous membranes
- lungs
- brain
- heart
- GIT, kidney
- muscles
necrotizing glomerulonephritis (90% of
patients)

No granulomatous inflammation
Lesions are similar to PAN, but spare
medium-sized and larger arteries
Macroscopic infarcts uncommon
Only infiltrating, fragmenting
neutrophils are seen in post-capillary
venules
leukocytoclastic vasculitis

aneurysm
rupture,
thrombose
MI
sudden death

IV immunoglobulin therapy and

Aspirin:
- lessens rate of coronary artery
dse. to only 4%

Major clinical features:

hemoptysis
hematuria
proteinuria
bowel pain or
bleeding
muscle pain or
weakness
palpable cutaneous
purpura

Pauci-immune injury:
little or no immunoglobulins
seen

pulmonary capillaritis

Associated with:
- asthma
- allergic rhinitis
- lung infiltrates
- peripheral hypereosinophilia
- extravascular necrotizing
granuloma

Triad:
1. Acute Necrotizing Granuloma
URT: ear, nose, throat, sinus
LRT
or both
2. Necrotizing or
Granulomatous Vasculitis
affects small to medium
vessels
(capillaries, venules,
arterioles, arteries)
most prominent in lungs
and upper airways
3. Renal disease:
- focal necrotizing
- crescenteric
glomerulonephritis

Vascular lesions similar to PAN or MP

but characteristically has granulomas
and eosinophils
ANCAs:
- present in less than
- mostly MPO-ANCA if ever
- probably responsible for
vascular manifestations

UR tract lesions:
- inflammatory sinusitis w/
muscosal granulomas
- ulcerative lesions of nose,
palate, or pharynx
rimmed by granulomas w/
geopgraphic patterns of
central necrosis and
vasculitis
Necrotizing Granuloma:
- surrounded by zone of
fibroblastic proliferation w/
giant cells and leukocyte
infiltrate
Multiple granulomas
coalesce
radiographically visible nodules that
can cavitate

Major Associations:
- cutaneous involvement
(palpable
purpura)
- GIT bleeding
- renal disease (primarily focal
and
segmental glomerulosclerosis)
Cardiomyopathy:
- d/t myocardial infiltrates and
eosinophils
involvement of heart in 60%
usual cause of death
M>F
Ave age: 40 y.o.
Classic features:
- persistent pneumonitis w/
bilateral nodular and cavitary
infiltrates (95%)
- chronic sinusitis (90%)
- muscosal ulcerationf of
nasopharynx (75%)
- renal disease (80%)
Other features:
- rashes
- muscle pains
- articular involvement
- mononeuritis or polyneuritis
- fever
17

Remission:
- negative test
- falling titers

Late stage:
- marked by extensive necrotizing
granulomatous involvement of
parenchyma
- alveolar hemorrhage
- lesions undergo progressive fibrosis
and organization

Rapidly fatal if untreated

80% die w/in 1 year
Tx: steroids, cyclophosphamide,
TNF-antagonists
chronic
remitting/ relapsing disease

Renal Lesions:
- early: focal necrosis w/ thrombosis of
isolated glom capillary loops (focal
and segmental necrotizing
glomerulonephritis)
- minimal parietal cell proliferation in
Bowmans capsule

Thromboangiitis
Obliterans (Buerger
Disease)
Exclusive to
cigarette smokers

Distinctive and leads to

vascular insufficiency

Usually before 35
y.o.
Common in:
- Israeli
- Indian
- Japanese
Tx:
- abstain from
smoking in early
stage
dramatic
relief

Tobacco
direct
endothelial cell toxicity OR
idiosyncratic immune
response
Patients have
hypersensitivity to injected
tobacco extracts
vessels
have IMPAIRED endothelium
dependent vasodilation
when challenged w/ Ach

Sharply, segmental, thrombosing,

acute, and chronic inflammation of
medium sized and small arteries
- principally, tibial and radial
arteries
- secondary extension to veins and
nerves of extremities

Thrombus contents:
small microabscesses made of
neutrophils surrounded w/
granulomatous inflammation
thrombus
recanalize

Genetic, assoc. w/ HLAhaplotype

Vasculitis Associated w/ Other Disorders:

-

Advanced glom lesions:

- diffuse necrosis
- parietal cell proliferation
crescenteric glomerulonephritis
Micro:
- acute and chronic inflammation
- luminal thrombosis

vasculitis that resembles hypersensitivity angiitis or classic PAN can be associated with:
o
RA, SLE
o
Cancer
o
Systemic illness
Mixed cryoglobinemia
Antiphospholipid antibody syndrome
Henoch-Schonlein purpura
Rheumatoid Vaculitis:
o
Occurs after long-standing, severe RA
o
Usually affects small and medium arteries
o
Leads to:
visual infarction
clinically significant aortitis
Therapeutically impt. to identify underlying pathology
o
Ex. Lupus vasculitis and antiphosholipid antibody syndrome are morphologically
similar

eventually organize and

Inflammation extends to contiguous

veins and nerves (rare in other
vasculitis)

Early:
- superficial nodular phlebitis
- cold sensitivity (Raynaud
type) in hands
- pain in instep of foot d/t
exercise
instep
claudication
Diff. from atherosclerosis:
- severe pain even at rest d/t
neuronal involvement
Chronic ulceration of toes, feet,
fingers
frank gangrene

Eventually, all three structures encased

in fibrous tissue

But have diff. treatments:

Anti-inflammatory therapy for lupus vascultis
Anticoagulant therapy: antiphospholipid Ab syndrome

Infectious Vasculitis:
localized arteritis
d/t direct invasion of infectious agents
o
bacteria or fungi
o
Aspergillus or Mucor species
Vascular Invasion:
o
Part of localized tissue infection (bacterial pneumonia or adjacent to abscess)
Can arise from hematogenous seeding of bacteria
Vascular Infections:
o
Weaken arterial walls
o
Culminates myotic aneurysm
o
Induce thrombosis and infarct
Inflammation induced thrombosis of meningeal vessels in bacterial meningitis cause
infarction of underlying brain

18

RAYNAUD PHENOMENON (kmanalastas)

exaggerated vasoconstriction of digital arteries and arterioles

paroxysmal pallor or cyanosis of the digits of the hands or feet

(infrequently, the nose, earlobes, or lips)
involved digits show red, white, and blue color changes from most proximal to most distal
(correlating with proximal vasodilation, central vasoconstriction, and more distal cyanosis)
Raynaud phenomenon may be a primary disease entity or be secondary to a variety of conditions:
PRIMARY
SECONDARY
previously called Raynaud disease
vascular insufficiency of the extremities
exaggeration of central and local
secondary to arterial disease:
vasomotor responses to cold or emotional
SLE
stresses
Scleroderma
affects 3% to 5% of the general population
Buerger
(more in young women)
atherosclerosis
structural changes in the arterial walls are
absent
Raynaud phenomenon may be the first
in the late course, intimal thickening can
manifestation of these conditions
appear
some 10% will eventually manifest an
course is usually benign
underlying disease
long-standing can result in atrophy of the:
skin
subcutaneous tissues
muscles
ulceration and ischemic gangrene are rare
VEINS AND LYMPHATICS
Varicose veins + phlebothrombosis/thrombophlebitis: at least 90% of clinical venous diseases
VARICOSE VEINS
abnormally dilated, tortuous veins
due to:
prolonged, increased intraluminal pressure
loss of vessel wall support
involves the superficial veins of the upper and lower leg
legs are dependent for prolonged periods

venous pressures can be markedly elevated (up to 10x)

venous stasis and pedal edema

(even in essentially normal veins: simple orthostatic edema)
10% to 20% of adult males and 25% to 33% of adult females develop lower extremity varicose
veins
obesity increases risk
higher incidence in women (elevated venous pressure in lower legs caused by pregnancy)
familial tendency toward premature varicosities has been noted
Clinical Features:
Incompetence of venous valves leads to stasis, congestion, edema, pain, and thrombosis
most disabling sequelae:
persistent edema in the extremity
ischemic skin changes, including stasis dermatitis and ulcerations
poor wound healing and superimposed infections chronic varicose ulcers
embolism from these superficial veins is very rare
TWO other sites:

Esophageal varices
Liver cirrhosis (less frequently, portal vein obstruction or hepatic vein thrombosis)

portal vein hypertension

opening of porto-systemic shunts

increase the blood flow into veins at the:

gastro-esophageal junction (esophageal varices)
rectum (hemorrhoids)
periumbilical veins (caput medusa)
Esophageal varices are the most important because rupture can lead to massive (even fatal)
upper gastrointestinal hemorrhage.
Hemorrhoids
can also result from primary varicose dilation of the venous plexus at the anorectal junction
(through prolonged pelvic vascular congestion due to pregnancy or chronic constipation)
may be a source of bleeding
can thrombose and get inflamed
prone to painful ulceration
THROMBOPHLEBITIS AND PHLEBOTHROMBOSIS
Deep leg veins site of more than 90% of cases
Additional sites:
In males: periprostatic venous plexus in males
In females: pelvic venous plexus (large veins in the skull and dural sinuses)
Portal vein thrombosis
Predisposing factors:
Peritoneal infections
peritonitis
appendicitis
salpingitis
pelvic abscesses
Thrombophilic conditions associated with platelet hyperactivity (polycythemia vera)
Deep venous thrombosis (DVT)
Predisposing factors:
prolonged immobilization resulting in decreased blood flow (most important)
postoperative state (another independent risk factor)
mechanical factors that slow venous return: CHF, pregnancy, and obesity
Systemic hypercoagulability often predisposes to thrombophlebitis.
In cancer patients (adenocarcinomas), hypercoagulability occurs as a paraneoplastic syndrome
related to elaboration of pro-coagulant factors by the tumor cell Migratory thrombophlebitis
(Trousseau sign): venous thromboses appear in one site, disappear, and then reoccur in other
veins
Local manifestations of thrombi (distal edema, cyanosis, superficial vein dilation, heat, tenderness,
redness, swelling, and pain) may be entirely absent, especially in bedridden patients.
In some cases, pain can be elicited by pressure over affected veins, squeezing the calf muscles,
or forced dorsiflexion of the foot (Homan sign), absence of these findings does not exclude a
diagnosis of DVT.
Pulmonary embolism: serious complication of DVT
In many cases, the first manifestation of thrombophlebitis is a pulmonary embolus.
Outcome depends on the size and number of emboli (can range from no symptoms to death)
SUPERIOR AND INFERIOR VENA CAVAL SYNDROMES
SUPERIOR VENA CAVAL SYNDROME
INFERIOR VENA CAVAL SYNDROME
caused by neoplasms that compress or
caused by neoplasms that compress or
invade the superior vena cava (SVC)
invade the inferior vena cava (IVC) or
bronchogenic carcinoma
by a thrombus from the hepatic, renal,
mediastinal lymphoma
or lower extremity veins that propagates
upward
19

 SVC obstruction produces a clinical

complex of:
marked dilation of veins of the
head, neck and arms
cyanosis
pulmonary vessels can also be
compressed respiratory distress

hepatocellular carcinoma
renal cell carcinoma
IVC obstruction induces:
marked lower extremity edema
distention of the superficial
collateral veins of the lower
abdomen
massive proteinuria (because of
renal vein involvement)

LYMPHANGITIS AND LYMPHEDEMA

Primary disorders of lymphatic vessels are extremely uncommon; secondary processes are much
more frequent and develop in association with inflammation or malignancies.
LYMPHANGITIS
acute inflammation when bacterial infections
spread into lymphatics
most common agents: group A -hemolytic
streptococci
lymphatics are dilated and filled with an
exudate of neutrophils and monocytes

infiltrates can extend through the vessel wall

into the perilymphatic tissues

in severe cases, (+) cellulitis or focal abscesses

clinically, red, painful subcutaneous streaks
(inflamed lymphatics), and painful
enlargement of draining lymph nodes (acute
lymphadenitis)
bacteria can pass the venous circulation
bacteremia or sepsis

LYMPHEDEMA
Primary lymphedema
due to an isolated congenital defect
(simple congenital lymphedema)
or as familial Milroy disease
(heredofamilial congenital lymphedema),
which causes lymphatic agenesis or
hypoplasia
Secondary or obstructive lymphedema
due to a blockage of a previously normal
lymphatic
obstruction can result from:
Malignant tumors obstructing
lymphatic channels or regional
lymph nodes
Surgical procedures that remove
regional groups of lymph nodes
Post-irradiation fibrosis
Filariasis
Post- inflammatory thrombosis and
scarring
increases hydrostatic pressure in the
lymphatics distal to the obstruction

increased interstitial fluid accumulation

increased deposition of interstitial connective

tissue

brawny induration or peau d'orange (orange

peel) appearance

ulcers (due to inadequate tissue perfussion)

milk accumulations of the lymph: chylous
ascites, chylothorax, chylopericardium
(caused by rupture of dilated lymphatics)

20