Path Lecture 40-41: Blood Vessel Pathology

Arterial Aneurysms & Dissections

10/22/13 9:10 PM
Blood Vessel Structure
x Tunica Intima
o Innermost layer composed of endothelial cells and
subendothelial matrix
x Tunica Media
o Smooth muscle, elastic fibers
o Internal elastic lamina separates the media and intima
o External elastic lamina separates the media and the
adventitia
x Tunica Adventitia
o Longitudinal ECM fibers
o Contains vasa vasorum
Blood vessels that supply blood to the cells of the
arteries

Types of Arteries
x Large Elastic Fibers
o Allow for expansion and recoil
x Medium Muscular Fibers (Smooth muscle cells)
o Vasoconstriction & dilation
x Small Arteries/Arterioles
o Increased resistance
o Decreased speed

o Allows for gas exchange in capillaries

Vascular Disease
x Cardiovascular disease is the leading cause of morbidity and
mortality in adults
x Pathology of vessel disorders can be divided into 2 categories
o Narrowing of Vessel Lumen
Leads to obstruction
Slow Stenosis
Arteriosclerosis
Acute stenosis
Thrombosis/embolism
o Weakening of the Vessel Wall
Leads to dilation and rupture
Aneurysm
Localized, abnormal dilation of a blood vessel
Makes vessel unable to recoil properly
Dissection
Tear within a vessel wall
Aneurysm Classification
x Morphology False vs. True
x Location Aortic (abdominal, thoracic), Intracranial
x Etiology
Morphology
x True Aneurysms
o Arterial wall is intact, but attenuated vascular dilation
Atherosclerotic, syphilitic, and congenital aneurysms
o Saccular, Fusiform
x False Aneurysms
o Breaks in arterial wall cause hematoma that communicates
with the intravascular space
Pulsating meatoma
Leaks at anastomoses

Location
Aortic
x Divided into thoracic aortic aneurysms, and abdominal aortic
aneurysms
x Most important predisposing factors
o Atherosclerosis AAA
o Hypertension Thoracic (Ascending)
o Marfans Syndrome AAA or thoracic
FBN1 mutation that affects microfibrils
Leads to poor elastin formation in tunica media
Leads to other problems such as lens dislocation,
curvature of spine, funnel chest, lung collapse
x Mechanisms of Aneurysm Formation
o Defect in vessel wall integrity
Loeys-Dietz Aortic Aneurysm
TGF- gene mutation (similar to Marfan)

Ehlers-Danlos Syndrome
Collage types I and III defect
Vitamin C Deficiency
Altered collagen cross-linking
o Proteolytic degradation of vessel wall
MMP
Inflammation recruits cells that release MMPs
Degradation of vessel walls, weakening of vessel
wall
Inflammation also reduces TIMP expression,
enhancing MMP action
o Cystic medial degeneration
Relates to events leading to smooth muscle loss
Fibrous deposition and degeneration of vessel wall
media
Often ischemic
Atherosclerosis and hypertensions
Shown below is elastin stain with * marking where
degeneration of elastic tissue has occurred

o Trauma
o Anatomic Malformations
o Vasculitis
o Infections
o Tertiary Syphilis
Thoracic
o Less common than AAA
o Etiology
Hypertension is the most common risk factor


o Sites

Marfan syndrome (weakens vessel wall)

of Involvement
Ascending 40-50%
Aortic Arch 10%
Descending 45-50%

Abomdinal Aortic Aneurysm (AAA)

o High risk groups
Men, smokers, >60 years old
o Etiologic Factors
Atherosclerosis is the most common cause
Marfan Syndrome (weakens vessel wall)
o Sites of Involvement
Infrarenal (90%) Just below renal arteries
Pararenal
Suprarenal
o Two important variants
Inflammatory
Results from idiopathic periaortic fibrosis and
inflammation
Inflammation weakens the vessel wall
Mycotic
Localized, irreversible arterial dilation due to
destruction of the vessel wall by infection
Can arise from:
x Septic emboli (endocarditis)
x Bacteremic seeding / inoculation
o Salmonella gastroenteritis
x Contiguous infection
o Signs/Symptoms
Asymptomatic
If symptoms are present
Abdominal discomfort
Can spread to groin, buttocks, legs & flanks
Pulsating sensation/mass in abdomen
o Clinical Complications
Rupture
Results in massive hemorrhage and hypotension
Risk related to size
x Aneurysms >5cm are managed aggressively
by surgical bypass
x Involves prosthetic grafts or endoluminal
stentss
Hypotensive shock

Cyanosis, mottling, altered mental status,

tachycardia
Obstruction
Ischemic injury of downstream tissues
Embolism
From atheroma or mural thrombus
Compression
Of adjacent structures
Intracranial (Berry Aneurysms)
x Most common kind of aneurysm in the brain
x Results from anatomic/congenital malformation
o Focal attenuation of tunica media and elastic lamina
x Sites of involvement
o Major bifurcations in Circle of Willis
o Most commonly occurs in the anterior communicating
artery bifurcation
x Sequelae
o Rupture/subarachnoid hemorrhage (90% risk of death)
o Aggravated by hypertension
Renal disease, vasculitis, drugs

Aortic Dissection
x Accumulation of blood between layers of the blood vessels (tunica
media) via tears in the tunica lamina

x
x
x
x

Most common to 40-60 year old men with hyptertension

Also in younger patients with CT diseases
Some are iatrogenic
o Diagnostic catheter, bypass surgery
Pathogenesis
o Hypertension is the major risk factor
Due to cystic medial degeneration
o Intimal tear allows blood flow to dissect through the media
and travel along the aorta distally

o Most common site is the ascending aorta

Classification of Aortic Dissections

o DeBakey Types
I Ascending and descending
II Ascending only
III Descending only
o Stanford Classifications
A All dissections involving ascending aorta, regardless
of site of origin

B All dissections NOT involving ascending aorta

Clinical Symptoms
o Sudden severe chest / upper back pain
Described as tearing, ripping, stabbing
Radiates to the neck or down the back
o Loss of Consciousness
o Different pulse rates in each arm (if it affects the arch)
o Shortness of breath
o Weakness/paralysis
o Sweating
Clinical Complications / Sequelae
o Rupture
Most common cause of death

Pericardial tamponade may occur if rupture is

proximal to the heart

o Retrgrade Extension (Proximal)

Aortic valve insufficiency
Myocardial Infarction

o Anterograde Extension (Distal)

Compression of aortic branches obstructing flow to
distal organs

Varicose Veins
x Abnormally dilated, tortuous, superficial veins of the lower
extremities
x Vascular dilation results from high intraluminal pressure and
loss of structural support
x Increased venous pressure can be caused by
o Obesity
o Pregnancy
Vena cava compressed by fetus
o After prolonged periods of standing
x Varicose dilation leads to incompetent venous valves
o Leads to stasis, edema, congestion, pain, and thrombosis
x Clinical Symptoms
o Stasis dermatitis & ulcerations
o Poor wound healing
o Superimposed infections
o Embolism from superficial veins is very rare

Portal Hypertension & Varices

x Increased portal pressure due to
o Cirrhosis
o Portal vein obstruction
o Hepatic vein thrombosis
x Leads to development of
o Porto-systemic collateral vessels (Shunts)
x Collateral vessels become prominent and dilated

o Gastroesophageal veins
o Umbilical veins
o Hemorrhoidal veins

Esophageal Varices
o Responsible for the main complications of portal hypertension
Massive upper GI hemorrhage and bleeding with
rupture

o Caput Medusa
Distended and engorged periumbilical veins radiating
across the abdominal wall

o Hemorrhoids
Dilation of anal veins

Internal or external depending on location relative to

dentate line
Caused by
Straining, Constipation
Sitting for long periods of time
Anal infections
Cirrhosis

Superior Vena Cava Syndrome

x Compression of superior vena cava results in venous flow
obstruction
x Clinical complications
o Dilation of head, neck, & arm veins
o Cyanosis
o Dilation/compression of pulmonary vasculature
Causes respiratory distress
x Bronchigenic carcinoma and mediastinal lymphoma are the
most common malignancies associated with SVCS
Inferior Vena Cava Syndrome
x Caused by malignancies that compress or invade the IVC
x Most commonly cased by:
o Hepatocellular carcinoma
o Renal cell carcinoma
o Also caused by extension from hepatic, renal, or lower
extremity vein thrombi
x IVC causes:
o Lower extremity edema
o Distension of the superficial collateral veins of lower abdomen
o Renal dysfunction
Deep Vein Thrombosis
x DVT is 3rd most common CV condition after CAD and stroke
x Virchows Triad
o Stasis
o Vessel wall injury
o Hypercoagulability
x Pulmonary embolism results form fragmentation of the venous
thrombus and causes arterial obstruction
Lymphangitis
x Acute inflammation of lymphatic vessels secondary to spread of
bacterial infection
o Group A -hemolytic strep is the most common cause

o Most commonly seen in children

Bacteria usually contained in lymph nodes
o Extension into venous circulation results in bacteremia or
sepsis
o Extension through vessel wall can produce cellulitis & focal
abscesses
Clinically
o Red, painful streaks along affected lymphatic paths
o Painful enlargement of lymph nodes (acute lymphadenitis)

Lymphedema
x Increase in the lymphatic hydrostatic pressure due to flow
obstruction
x Primary Lymphedema
o Congenital
o Results form lymphatic agenesis or hypoplasia
x Secondary Lymphedema
o Blockage of normal lymphatics due to
Malignant involvement
Surgical procedures that remove regional groups of
lymph nodes
Eg) Axiallary lymph nodes in radical mastectomy
Post-irradiation fibrosis
Filariasis
Post-inflammatory thrombosis and scarring
x With time, overlying skin becomes edematous, indurated, and
ulcerated
o Advaced cases can result in massive engorgement of the
affected extremity
Decrease / loss of function (lymphostatic
elephantiasis)

x
x

Rupture of obstructed lymphatics can also lead to extensive lymph

accumulations in body cavities
Histosection shows replacement of lymph node tissue by canerous
tissue obstruction

Vasculitis
x Inflammation of the vessel wall with deleterious consequences on
downstream tissues
x Diverse disease group categorized by etiology and size of vessel
involved
Most common etiologic mechanisms
x Noninfetious
o Immune-mediated inflammation
x Infectious
o Colonized by infectious pathogens
x Physical/Chemical Injury
o Irradiation, mechanical trauma, toxins
x Distinction of etiology is important for management
Noninfectious Vasculitis pathophyisologic mechanisms
x Immune complex deposition
o Circulating antigen-antibody complexes deposit in vascular
beds and cause an inflammatory response
o Can be associated with
Autoimmune disorders
SLE
Drug hypersensitivities
Penicillin
Viral infections
HBV
x Anti-neutrophil cytoplasmic antibodies
o ANCAs
Diverse group of autoantibodies directed against
neutrophils, monocyte lysososmes, and endothelial cells
Classified based on intracellular distribution and target
antigens
Perinuclear (p-ANCA)
x Anti-myeloperoxidase (MPO-ANCA)
Cytoplasmic (c-ANCA)
x Anti-Proteinase-3 (PR3-ANCA)

o ANCA titers are measured by ELISA studies

Type is determined by indirect immunofluorescence

Titers reflect degree of inflammatory activity and
recurrence (clinical management)
o ANCAs directly activate neutrophils
Stimulates release of ROS and proteolytic enzymes
Causes endothelial cell damage
o Pathogenesis poorly understood
ANCA production induced by cross-reactivity
Predisposing inflammatory stimuli upregulate MPO/PR3

x
x

Anti-endothelial cell antibodies

o Kawasakis Disease
For most vasculitses a specific causative agent has not yet been
defined
o Therefore, site of involvement is an important clue in
diagnosis

Vessel Size Involvement

Giant Cell (Temporal) Arteritis

x Most common form of vasculitis in the US
x Affects adults >50y
o Particularly the elderly
x Chronic, granulomatous inflammation of:
o Large vessels of the head
Temporal, vertebral & ophthalmic arteries
x Ophthalmic involvement
o Can lead to permanent blindness
x Sensitive to treatment with corticosteroids and anti-TNF in
refractory cases
o Prompt diagnosis is important!
x Etiology Uncertain
o T cell response against a vessel antigen
o Release of cytokines, TNF, and humoral response
o Anti-endothelial Ab
x Morphologic Findings
o Granulomatous inflammation of media
o Intimal fibrosis

o Disruption of internal elastic lamina

Clinical Features
o Fever, fatigue, weight loss
o Headaches
o Facial Pain
o Pain on palpation along the course of the superficial temporal
artery
o Ocular Symptoms
Diplopia vision loss
Diagnosis
o Clinical findings
o Elevated ESR (erythrocyte sedimentation rate?)
o Histiologic confirmation

Takayasu Arteritis
x Granulomatous vasculitis of the medium-large arteries and
aorta
o Almost targets the aorta
Aortic Arch and great vessels (60%)
Distal aorta and branches (30%)
x To distinguish from giant cell arteritis, use AGE
o <50y = Takayasu Aortitis
o >50y= Giant cell Aortitis
x Variable course (slow or rapid)
x Diagnosis
o Clinical findings
o Elevated ESR
x Treatment
o Corticosteroids

Clincial Findings
o Initial symptoms nonspecific
o Progression leads to:
Pulseless disease
Reduced BP and pulses in arms
Ocular disturbances (visual defects, retinal
hemorrhages, total blindness)
Neurologic Deficits
Pulmonary hypertension (pulmonary artery)
Narrowing of coronary ostia
Can lead to MI
Systemic hypertension (renal arteries)

Polyarteritis Nodosa (PAN)

x Segmental necrotizing transmural vasculitis
x Small-medium sized arteries
x Involves visceral vessels
o Kidney, liver, heart, GI
x Pathogenesis unknown, but 3 categories recognized
o Idiopathic
o Cutaneous
o HBV associated
Cross-reactivity with IC
x Affects all ages, typically young adults
x Variable clinical course
o Episodic with long free intervals
x Clinical findings
o Peripheral ischemia in skin & nerves neuritis
o Hypertension (renal vessels)
Renal failure Major cause of death
o Abdominal pain & melena
From GI ischemia
o Fatal if untreated Usually during acute attack
Quick progression
Treatment based on corticosteroids and
cyclophosphamide (anti-inflammatories)

Acute Stage
o Transmural inflammation (neutrophils, eosinophils,
monocytes)
o Fibrinoid necrosis & thrombosis

Chronic Stage
o Fibrous thickening (scarring) of vessel wall

x
x

Different stages can be seen in a given patient

Weakening of the arterial wall by inflammation leads to
o Aneurysms
o Impaired perfusion ischemia

Kawasaki Disease
x Disease of early childhood (<4y) affecting large-medium and
small arteries
o Will see kids with MIs
o Affects coronary arteries aneurysm/rupture
thrombosis acute MIs
x Leading cause of acquires heart disease in children
x Pathophysiology
o Formation of autoantibodies to endothelial & smooth
muscle cells
B cell activation and cytokine release
o T cells mediate delayed-type hypersensitivity reaction
o Infectious agents are more likely the trigger (cross-reactivity)
x Clinical Findings
o Conjunctival and oral erythema/ulcer

o Edema of hands and feet

Erythema in palms and soles
o Desquamative Rash (shedding of skin)
o Cervical lymphadenopathy
o Up to 20% of untreated patients develop cardiovascular
disease
Aneurysm & rupture
Thrombosis
MI Sudden death
Treatment
o IV Ig therapy
o Aspirin
Normally contraindicated in children


Microscopic Polyangitis
x Necrotizing vasculitis of capillaries, arterioles, and venules
x Broad systemic involvement of:
o Skin, mucous membranes, lungs, brain, heart, GI tract,
kidney & muscle
x Necrotizing glomerulonephritis
x Pulmonary capillaritis
x Pathogenesis
o Associated with P-ANCA (MPO-ANCA)
o IC deposition
Antibody response to drug (penicillin)
bacteria (strep) or tumor protein
antigens
o Recruitment and activation of neutrophils
Leukocytoclastic vasculitis
Destructive infiltration and degranulation of
neutrophils
o Segmental fibrinoid necrosis of tunica media
Without granulomatous inflammation

Treatment
o Cyclophosphamide & steroids
o Renal and brain involvement are difficult to treat

Wegner Granulomatosis
x Necrotizing granulomatous vasculitis of small/medium sized
arteries
x Affects males > females, usually in 40y
x Clinically resembles PAN
o Distinction is in the respiratory system
o Respiratory system involved in Wegner
Not involved in PAN
x Pathophysiology
o T cell mediated hypersensitivity reaction (to inhaled agents)
o PR3-ANCAs (C-ANCAs) present
o Responds to immunosuppressive therapy
o 80% of untreated patients die within 1 year

Clinical Features
o Chronic sinusitis
o Nasopharyngeal ulceration
o Persistent pneumonitis
o Renal disease, hematuria, failure
o Rashes, muscle pains, articular involvement, neuritis, fever
Morphologic Features
o Necrotizing granulomas
Central necrosis
Fibroblastic proliferation
Giant cell reaction
Mononuclear infiltrate
Glomeruli of kidney affected

Thromboangiitis Obliterans (Buerger Disease)

x Vasculitis of medium and small arteries
o Especially tibial & radial arteries
x Most commonly seen in young cigarette smokers (<35y)
x Pathogenesis
o Direct endothelial cell toxicity to tobacco component
Patients are hypersensitive to tobacco extracts
o Impaired endothelial-dependent vasodilation when given Ach
o Clinical Features
Raynaud
Claudication induced by exercise
Severe pain at rest
Due to neural involvement
Unhealing ulcers of toes, feet, fingers

x
x

Gangrene

Vascular insufficiency gangrene

Smoking cessation reduces progression

Vasculitis Assocaited with other Disease

x RA
x SLE
x Mixed cryoglobulinemia
x Antiphospholipid Antibody Syndrome
x Henoch-Schnlein purpura
Infectious Vasculitis
x Vessel wall inflammation due to colonization by infectious
pathogens
o Subsequent immune complex deposition and Ab crossreactivity
x Can lead to weakening of vessel wall and mycotic aneurysms
x Examples
o Bacterial pneumonia pulmonary hemorrhage
o Bacterial meningitis brain infarction
o Aspergillus & Mucor

Vasoinfective fungi

Vascular Hyper-reactivity
x Not vasculitis, but I put it here
x Raynaud Phenomenon
o Recurrent vasospasms of the fingers and toes in response to
stress or cold
o Primary Raynaud (Raynaud Disease)
Vasospasm with no association of systemic illness
o Secondary Raynaud
Vasospasm associated with autoimmune disease
Scleroderma
Mixed CT disease
o 3 Phases of color change
Initial white (vasoconstriction)
Blue (cyanosis)
Red (rapid blood reflow)
o Changes are reversible
Must be distinguished from the
irreversible causes of ischemia
such as vasculitis &
thrombosis
o Most commonly affects fingers and
toes
Can also affect nose, ears, and tongue
o Pathophysiology unknown
Structural vessel wall abnormalities
Deficiencies in autonomic control
o More prevalent in women in 20-30s

Hemangioma
x Tumors of blood-filled vessels
x Often present at birth
x Most commonly seen in head and neck
o Can also be present in internal organs such as liver
x Classification based on histological appearance
o Capillary Hemangiomas
Strawberry Hemangiomas
Found in newborns
Disappear on their own

Pyogenic Granulomas

Cavernous Hemangiomas
Composed of larger vascular channels
Circumscribed, locally destructive
Do not regress on their own
Von-Hippel-Lindau disease they are present in
the retina, CNS, pancreas, and liver


Lymphangiomas
x Equivalent to hemangiomas in the lymphatic system
x Capillay (simple)
x Cavernous (Cystic Hygromas)
o Can present as huge tumors in the head, neck, or axilla of
newborns
o Unencapsulated growth pattern
Makes them difficult to excise
Penetrate into muscles and other structures

Bacillary Angiomatosis
x Vascular proliferation secondary to Bartonella infection
o Affects immunocompromised patients
x Bartonella henselae
o Cat-scratch disease
x Bartonella Quintana
o Trench fever transmitted by body lice
o Silver staining below highlights bacilli in bacillary angiomatsis
in an AIDS patient

Kaposi Sarcoma
x Caused by HHV-8
x Most commonly affects AIDS patients
o An AIDS-defining illness
x Elderly and immunosuppressed also affected
x Viral infection leads to uncontrolled cellular proliferation by
disruption of Cyclin D & P53
x Cutaneous lesions progress from patches plaques nodules

Angiosarcoma
x Malignant vascular neoplasm
x Composed of rapidly proliferating, infiltrating, anaplastic cells
x Rare malignancy
o No association to special settings
x Hepatic Angiosarcomas are associated with exposure to
o Vinyl chloride monomer (VCM)
o Polyvinyl chloride (PVC)
o Arsenic containing insectisides and Thorotrast
x Angiosarcoma can occur during treatment for primary breast
carcinoma
o Cutaneous angiosarcoma after breast lumpectomy, axillary
lymph node dissection and radiotherapy