CHAPTER 11

!
BLOOD VESSELS

!!
CONGENITAL ANOMALIES
• Developmental/berry aneurysms
• AV fistulas
• Fibromuscular dysplasia
• The uniform vascular response to any type of injury is intimal thickening.
!
HYPERTENSION
• Essential (90 – 95%)
• Secondary (5 – 10%)
• Renal – acute GN, chronic renal disease, polycystic disease, renal artery stenosis, vasculitis, renin-
producing tumors
• Endocrine – adrenocortical hyperfunction, exogenous hormones, pheo, acromegaly, thyroid
disease, pregnancy induced
• Cardiovascular – coarctation, PAN, volume overload, increased cardiac output, rigid aorta
• Neurologic – psychogenic, increased ICP, OSA, acute stress
!
• Blood pressure determined by cardiac output and peripheral vascular resistance (BP = CO x PVR)
• Kidneys regulate BP as follows:
• Renin-angiotensin system
• Kidney produces a variety of vasodilatory substances
• GFR controls sodium resorption
• Natriuretic peptides act on the distal tubule to increase sodium excretion
• Rare single gene mechanisms of increased BP include 11b-hydroxylase, 17a-hydroxylase, and mutations
in proteins affecting sodium resorption (Liddle syndrome and Na transporter)
!
Vascular pathology in hypertension:
• Hyaline arteriolosclerosis and nephrosclerosis
• Hyperplastic arteriolosclerosis
!
CLASSIFICATION OF ARTERIOSCLEROSIS:
• Arteriolosclerosis – hyaline and hyperplastic
• Monckeberg medial sclerosis
• Atherosclerosis
!
MAJOR RISK FACTORS FOR ATHEROSCLEROSIS:
• Nonmodifiable:
• Age
• Gender
• Family hx
• Genetics
• Modifiable:
• Hyperlipidemia
• Hypertension
• Smoking
• Obesity
• DM
 • CRP
• Additional risk factors:
• inflammation
• hyperhomocysteinemia
• metabolic syndrome
• lipoprotein a
• hemostatic factors
!
PATHOGENESIS OF ATHEROSCLEROSIS
• Endothelial injury → increased adhesiveness and procoagulant activity
• Accumulation of lipoproteins
• Monocyte migration into intima followed by transformation to macrophages and foam cells
• Growth factor release from macrophages and platelets inducing sm cell recruitment
• Sm proliferation and ECM production
• Lipid accumulation
• Fatty streak – lipid filled foamy macrophages and SMC that protrude into vascular lumen
• Atherosclerotic plaque – cells (sm, macs, T-cells), ECM (collagen, elastic fibres, proteoglycans), and lipid
• is a raised white-yellow intimal based lesion - composed of superficial fibrous caps containing
SMC, inflammatory cells and dense ECM overlying necrotic cores, contain gin dead cells, lipid,
cholesterol, foam cells and plasma proteins; small BV proliferate at the intimal-medial interface
• plaques are complicated when have calcification, hemorrhage, fissuring or ulceration (which are
often assoc with local thrombosis, medial thinning, cholesterol emboli and aneurysmal dilatation)
!
Clinical consequences of plaques:
• Rupture, ulceration, erosion
• Hemorrhage into the plaque
• Emboli
• Aneurysm formation
!
Major consequences of atherosclerotic disease
• MI
• Stroke
• Aneurysms
• PVD
!
CLASSIFICATION OF CALCIFICATIONS:
• Associated with normal serum calcium
• Dystrophic – normal serum Ca, response to tissue damage
• Ehlers-Danlos syndrome, pseudoxanthoma elasticum, vascular calcifications, crystal
deposition disorders, and calcification resulting from neurologic disorders
• Calcinosis
• Subcutaneous tissue, skin, connective tissue
• Calcinosis universalis, calcinosis circumscripta, scleroderma, dermatomyositis,
and systemic lupus erythematosus
• Associated with elevated serum calcium
• Metastatic – involves normal tissues
• Elevated PTH – hyperplasia, adenoma, carcinoma
• Normal PTH – neoplasms, milk-alkali syndrome, hypervitaminosis D, tumoral calcinosis,
calciphylaxis
!
Aneurysms and Dissections:
• morbidity and death due to:
• rupture
 • impingement on adj structures
• occlusion of proximal vessels by extrinsic pressure or superimposed thrombosis
• embolism from a mural thrombus
• Pathogenesis of Aneurysms:
• poor intrinsic quality of vessel matrix (eg. collagen disorders)
• imbalance of matrix synthesis and degradation
• loss of medial SMC or change in SMC matrix synthesis (cystic medial necrosis)
• most common cause of aortic aneurysms:
• atherosclerosis and HTN
• others: syphillis, trauma, vasculitis, congenital defects (berry aneurysms)
• infections (mycotic aneurysms)
• AAA’s:
• risk of rupture increases with diameter (low if <5 cm, when 5-6 cm 11% risk of rupture per year,
when >6 cm 25% risk of rupture per year)
!
• Aortic Dissection occurs in 2 main groups:
1. men with HTN b/w ages of 40 and 60 (cystic medial necrosis)
2. younger pts with CTD (eg. Marfan’s)
• others: trauma, iatrogenic, pregnancy assoc
• dissection is uncommon in atherosclerosis or other conditions assoc with medial scarring
(fibrosis limits propagation of dissection)
• Complications of Dissection depend on portion affected:
• type A (more proximal) - more common and dangerous
• type B (start after subclavian art)
!!
!
VASCULITIS
• 2 main mechanisms: infectious versus immune-mediated
• other causes: physical and chemical injury (eg, radiation, trauma, toxins)
!
• Immune Complex-Associated Vasculitis:
• injury arises from Ag-Ab circulating complexes that deposit in vessels and subsequent
complement activation or recruitment of Fc-receptor bearing cells
• often underlies drug hypersensitivities and viral infections
!
• ANCA associated (aka, pauci immune):
• Ab’s directed against constituents of neutrophil primary granules, monocyte lysosomes, or
endothelial cell:
• Anti-MPO - directed against lysosomal constituent involved in generating free oxygen
radicals (also called peri-nuclear ANCA (p-ANCA)
• seen in MPA and CSS
• Anti-proteinase 3 - directed against a neutrophil azurophilic granule constituent cells
cytoplasmic ANCA (c-ANCA)
• often assoc with WG
• these autoAb’s can directly activate pmn’s and cause release of proteolytic enzymes and ROS that
damage endothelium
!
• Anti-Endothelial Cell Ab’s:
• e.g.. in Kawasaki disease
!!
!!
UPDATED 2012 CHAPPEL HILL CLASSIFICATION OF VASCULITIDES
!
Large vessel vasculitis (LVV)
Takayasu arteritis (TAK): granulomatous, med-large arteries
Giant cell arteritis (GCA)
Medium vessel vasculitis (MVV)
Polyarteritis nodosa (PAN): systemic necrotizing, small-med arteries; IC deposition; lungs are spared
Kawasaki disease (KD): med-large vessels, T-cell hypersensitivity (Ag unknown)
Small vessel vasculitis (SVV)
ANCA-associated vasculitis (AAV)
Microscopic polyangiitis (MPA): necrotizing vasc of arterioles, caps, venules - most are
pauci immune, but some are assoc with IC (drugs, bugs, tumors) -
leukocytocastic vacs
Granulomatosis with polyangiitis (Wegener’s) (GPA): necrotizing vasculaitis assoc with nec
or gran vacs of small-med vessels mostly in upper lung and upper a/w; nec
gran of upper and lower reap tract and GN
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) - small vessel
necrotizing vasculitis assoc with asthma, allergic rhinitis, periphery
eosinophilia and necrotizing granulomas
Immune complex vasculitis SVV
Anti-glomerular basement membrane (anti-GBM) disease
Cryoglobulinemic vasculitis (CV)
IgA vasculitis (Henoch-Schonlein) (IgAV)
Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis)
Variable vessel vasculitis (VVV)
Bechet's disease (BD)
Cogan’s syndrome (CS)
Single -organ vasculitis (SOV)
Cutaneous leukocytoclastic angiitis
Cutaneous arteritis
Primary CNS vasculitis
Isolated aortitis
Others
Vasculitis associated with systemic disease
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others
Vasculitis associated with probable etiology
Hepatitis C virus-associated cryoglobulimemic vasculitis
Hepatitis B virus-associated vacuities
Syphilis-associated aortitis
Drug-associated ANCA-associated vasculitis
Cancer-associated vasculitis
Others
!!
!!
!!
!!
!
 Overview and Classification of Systemic Vasculitides
Type Clinical Features Serology Pathologic Features Glomerular Lesion
Large Vessel Vasculitis (Large, Aorta and Major Branches)
Giant cell Polymyalgia ANCA negative Commonly temporal arteritis, Ischemic changes; amyloidosis
arteritis: Usually > rheumatica (50%), mononuclear cell infiltration with
50 years, elderly, mostly head and multinucleated giant cells
M:F = 1:2-6 neck symptoms
Takayasu arteritis: Initial nonspecific ANCA negative Granulomatous panarteritis with Ischemic changes; mesangial
Usually 30-50 symptoms, later multinucleated giant cells or focal proliferative GN
years, M:F = 1:8 ischemic effects of
tissues
Medium-sized Vessel Vasculitis (Medium-sized Arteries)
Polyarteritis Multisystemic, Rarely p- Fibrinoid necrotizing arteritis, Ischemic changes; rare pauci-
nodosa: Peak: hypertension, ANCA(+); transmural, healed lesions, stenosis, immune crescentic GN
5th-7th decade, symptoms of organ hepatitis B virus aneurysm formation
M:F = 2:1 ischemia (+)
Kawasaki disease: Mucocutaneous Systemic atypical Depending on stage: Acute Rare mesangial proliferative
< 3 years in most lymph node cytoplasmic neutrophilic arteritis, aneurysm GN; patchy interstitial
cases; M:F = 5:1 syndrome; ANCA(+) formation, chronic inflammation, and inflammation
coronary artery scarring
vasculitis
Small Vessel Vasculitis (Small Arteries, Arterioles, Venules, Capillaries)
Granulomatosis Multisystemic, Antiproteinase-3 Necrotizing, vascular, or extravascular Pauci-immune crescentic GN,
with polyangiitis upper airway, lung ANCA(+) (> granulomatous inflammation acute, subacute, and chronic
(Wegener): Any and kidneys (90%), 75%),
age, peak: 30-50 rapidly progressive antimyeloperoxid
years; M > F renal failure, no ase ANCA(+) (<
asthma 25%)
Microscopic Multisystemic, Antimyeloperoxi Fibrinoid necrotizing vasculitis Pauci-immune crescentic GN
polyangiitis: Any kidney (90-100%), dase ANCA(+)
age, peak: 50 nephritic (60%),
years; M = F syndrome, rapidly antiproteinase-3
progressive renal ANCA(+) (15%)
failure, no asthma
Churg-Strauss Multisystemic, ANCA(+) Eosinophil-rich fibrinoid necrotizing Commonly mesangial,
syndrome: Peak: asthma, (40-70%), mostly vasculitis and granulomatous occasional pauci-immune,
40-60 years; M = F eosinophilia, renal anti-MPO ANCA inflammation proliferation, focal GN with
manifestations in < crescents
30% of cases
Henoch-Schönlein Multisystemic, Sometimes Leukocytoclastic vasculitis, dominant Mesangial or endocapillary
purpura: 90% kidney, lung, elevated serum IgA and C3 deposits proliferation ± crescents and
before 10 years; M gastrointestinal IgA level, normal IgA deposits
> F; adult/ tract complements,
secondary ANCA(-)
Mixed Multisystemic; skin Elevated Leukocytoclastic vasculitis with Membranoproliferative GN ±
cryoglobulinemic and kidney monoclonal IgM cryoprecipitates, IgM κ, IgG, and C3 crescents and cryo deposits
vasculitis: Adults frequently involved κ rheumatoid deposits
factor, most
HCV(+)
Systemic lupus Multisystemic, skin ANA(+), Necrotizing vasculitis Immune complex GN ±
erythematosus: and kidney (90%) dsDNA(+), crescents; rarely, pauci-
Any age, M:F = sometimes immune crescentic GN
1:9 ANCA(+)

!!
!!
!
Vascular Diseases Mimicking Vasculitis
Disease Location Pathology Inflammation Pathogenesis
Antiphospholipid All calibers of arteries Fibrin or organizing Rare or none Antiphospholipid
antibody syndrome and veins, capillaries vascular thrombi, focal antibodies or lupus
recanalization anticoagulant
Thrombotic Small arteries, arterioles, Endothelial swelling, None Abnormalities of
microangiopathy capillaries intimal mucoid change, ADAMTS 13; immune
fibrin and organizing complexes; drug induced
thrombi; intact elastic
lamina
Atheroembolism All calibers of arteries up Luminal occlusion by None; foreign body giant Embolic phenomenon
to capillaries crystalline cholesterol cell reaction in older from atheromas of larger
clefts ± thrombosis lesions arteries
Amyloid angiopathy Medium and small Congo red positive, None AL amyloid or
arteries, arterioles, and amorphous, acellular, monoclonal lambda or
capillaries vascular amyloid deposits kappa chains; rarely
other forms of amyloid
Bacterial endocarditis Small arteries, arterioles, Local ischemic changes, Sometimes Emboli from cardiac
and capillaries occasional infection- valvular vegetations,
related inflammation, focal which may be bland or
glomerulonephritis in septic
kidney
Atrial myxoma Small arteries, arterioles, Luminal occlusion by None Embolic phenomenon
(intracardiac tumor) and capillaries fragments of myxoma with from fragments of
ischemic tissue changes cardiac tumor

!!
!
Kaposi Sarcoma
• intermediate grade tumor; 4 varieties:
3. Chronic/classic/European KS:
• elderly men of Eastern Euro or Med descent, not assoc with HIV
• lesions are red-purple cutaneous plaques and nodules on lower extremities, rare visceral
involvement
• tx: surgical resection adequate, excellent px
4. Lymphadenopathic/African/endemic KS:
• same geo location as Burkitts, not assoc with HIV
• sparse cutaneous lesions
• KS mainly in LN’s with occasional visceral involvement that can be aggressive
• tx: rads and/or chemo effective
5. Transplant-associated KS:
• immunosuppression with nodal, mucosal, and visceral involvement (can be aggressive
and fatal); lesions may regress with cessation of immunosuppression
6. AIDS-associated (epidemic) KS:
• anywhere on skin and mucous membranes, LN, GI tract, or viscera
• tx: antiretrovirals helpful; INF-α, angiogenesis inhibitors, blockade of intracellular kinase
pathways
• Pathogenesis: >95% lesions are infected with HHV-8 (aka KSHV)
• 3 stages of lesions:
1. Patches
2. Raised plaques
3. Nodular lesions